Compounds to treat Alzheimer&#39;s disease

ABSTRACT

The present invention is substituted amines of formula (X) 
                         
and of the formula (X′)
 
                         
useful in treating Alzheimer&#39;s disease and other similar diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to the following provisionalapplications: U.S. provisional application Ser. No. 60/215,323, filedJun. 30, 2000; U.S. provisional application Ser. No. 60/252,736, filedNov. 22, 2000; U.S. provisional application Ser. No. 60/255,956, filedDec. 15, 2000; U.S. provisional application Ser. No. 60/268,497, filedFeb. 13, 2001; U.S. provisional application Ser. No. 60/279,779, filedMar. 29, 2001; and U.S. provisional application Ser. No. 60/295,589,filed Jun. 4, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to compounds useful in treatment ofAlzheimer's disease and similar diseases.

2. Description of the Related Art

Alzheimer's disease (AD) is a progressive degenerative disease of thebrain primarily associated with aging. Clinical presentation of AD ischaracterized by loss of memory, cognition, reasoning, judgement, andorientation. As the disease progresses, motor, sensory, and linguisticabilities are also affected until there is global impairment of multiplecognitive functions. These cognitive losses occur gradually, buttypically lead to severe impairment and eventual death in the range offour to twelve years.

Alzheimer's disease is characterized by two major pathologicobservations in the brain: neurofibrillary tangles and beta amyloid (orneuritic) plaques, comprised predominantly of an aggregate of a peptidefragment know as A beta. Individuals with AD exhibit characteristicbeta-amyloid deposits in the brain (beta amyloid plaques) and incerebral blood vessels (beta amyloid angiopathy) as well asneurofibrillary tangles. Neurofibrillary tangles occur not only inAlzheimer's disease but also in other dementia-inducing disorders. Onautopsy, large numbers of these lesions are generally found in areas ofthe human brain important for memory and cognition.

Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloidogenic plaques and vascular amyloid angiopathy alsocharacterize the brains of individuals with Trisomy 21 (Down'sSyndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type (HCHWA-D), and other neurogenerative disorders. Beta-amyloidis a defining feature of AD, now believed to be a causative precursor orfactor in the development of the disease. Deposition of A beta in areasof the brain responsible for cognitive activities is a major factor inthe development of AD. Beta-amyloid plaques are predominantly composedof amyloid beta peptide (A beta, also sometimes designated betaA4). Abeta peptide is derived by proteolysis of the amyloid precursor protein(APP) and is comprised of 39–42 amino acids. Several proteases calledsecretases are involved in the processing of APP.

Cleavage of APP at the N-terminus of the A-beta peptide bybeta-secretase and at the C-terminus by one or more gamma-secretasesconstitutes the beta-amyloidogenic pathway, i.e. the pathway by which Abeta is formed. Cleavage of APP by alpha-secretase produces alpha-sAPP,a secreted form of APP that does not result in beta-amyloid plaqueformation. This alternate pathway precludes the formation of A betapeptide. A description of the proteolytic processing fragments of APP isfound, for example, in U.S. Pat. Nos. 5,441,870; 5,721,130; and5,942,400.

An aspartyl protease has been identified as the enzyme responsible forprocessing of APP at the beta-secretase cleavage site. Thebeta-secretase enzyme has been disclosed using varied nomenclature,including BACE, Asp, and Memapsin. See, for example, Sinha et.al., 1999,Nature 402:537–554 (p501) and published PCT application WO00/17369.

Several lines of evidence indicate that progressive cerebral depositionof beta-amyloid peptide (A beta) plays a seminal role in thepathogenesis of AD and can precede cognitive symptoms by years ordecades. See, for example, Selkoe, 1991, Neuron 6:487. Release of A betafrom neuronal cells grown in culture and the presence of A beta incerebrospinal fluid (CSF) of both normal individuals and AD patients hasbeen demonstrated. See, for example, Seubert et al., 1992, Nature359:325–327.

It has been proposed that A beta peptide accumulates as a result of APPprocessing by beta-secretase, thus inhibition of this enzyme's activityis desirable for the treatement of AD. In vivo processing of APP at thebeta-secretase cleavage site is thought to be a rate-limiting step in Abeta production, and is thus a therapeutic target for the treatment ofAD. See for example, Sabbagh, M., et al., 1997, Alz. Dis. Rev. 3, 1–19.

BACE1 knockout mice fail to produce A beta, and present a normalphenotype. When crossed with transgenic mice that overexpress APP, theprogeny show reduced amounts of A beta in brain extracts as comparedwith control animals (Luo et. al., 2001 Nature Neuroscience 4:231–232).This evidence further supports the proposal that inhibition ofbeta-secretase activity and reduction of A beta in the brain provides atherapeutic method for the treatment of AD and other beta amyloiddisorders.

Published PCT application WO/0047618 entitled “Beta-Secretase EnzymeCompositions and Methods” identifies the beta-secretase enzyme andmethods of its use. This publication also discloses oligopeptideinhibitors that bind the enzyme's active site and are useful in affinitycolumn purification of the enzyme. In addition, WO/0077030 disclosestetrapeptide inhibitors of beta-secretase activity that are based on astatine molecule.

Various pharmaceutical agents have been proposed for the treatment ofAlzheimer's disease but without any real success. U.S. Pat. No.5,175,281 discloses 21-aminosteroids as being useful for treatingAlzheimer's disease. U.S. Pat. No. 5,502,187 discloses bicyclicheterocyclic amines as being useful for treating Alzheimer's disease.

U.S. Pat. Nos. 4,616,088 and 4,665,193 discloses hydroxyethylaminecompounds as anti-hypertensive agents due to their ability to inhibitrenin.

U.S. Pat. No. 4,636,491 discloses various tetrapeptides which are usefulas renin inhibitors.

U.S. Pat. No. 4,749,792 discloses amino compounds useful as analgesicsbecause of their ability to inhibit an enkephalin-degradingaminopeptidase.

U.S. Pat. No. 5,142,056 discloses peptide derivatives with aC₂-symmetric dihydroxyethylene core as retroviral protease inhibitors.

U.S. Pat. Nos. 5,461,067 and 5,753,652 disclose the synthesis ofretroviral protease inhibitors.

U.S. Pat. No. 5,475,138 and 5,631,405 disclose processes and variousintermediates useful in the synthesis of selected protease inhibitors.

U.S. Pat. No. 5,502,061 discloses HIV protease inhibitors containing anunsaturated carbocycle or heterocycle at the C-terminus.

U.S. Pat. No. 5,545,640 discloses compounds which inhibit HIV proteaseactivity.

U.S. Pat. No. 5,516,784 discloses compounds active against retroviruses,including HIV.

U.S. Pat. No. 5,602,175 discloses hydroxyethylamine compounds asretroviral protease inhibitors.

U.S. Pat. No. 5,631,405 discloses a process for the formation ofintermediates useful in the synthesis of selected protease inhibitors.

U.S. Pat. No. 5,733,882 and International Publications WO 93/02057 andWO 93/17003 disclose dipeptide analogs as retroviral proteaseinhibitors.

U.S. Pat. No. 5,760,076 discloses hydroxyethylamino sulfonamidecompounds as retrovirus protease inhibitors.

U.S. Pat. No. 5,807,870 discloses hydroxyethylamine compounds for theinhibition of HIV protease.

U.S. Pat. No. 5,827,891 discloses HIV protease inhibitors.

U.S. Pat. No. 5,830,897 discloses hydroxyethylamino sulfonamidecompounds as retrovirus protease inhibitors.

U.S. Pat. No. 5,831,117 discloses a process and intermediates useful inretroviral protease inhibitor intermediates.

U.S. Pat. No. 5,847,169 discloses a process for preparing aminoepoxidesinvolving the activation of the terminal hydroxyl of an aminodiol.

U.S. Pat. No. 5,849,911 discloses hydroxyethylamine HIV proteaseinhibitors which form hydrazines with one of the amino groups; thisamino group must also be alkylated.

U.S. Pat. No. 5,922,770 discloses peptide derivatives which are usefulin treating disorders resulting from a deficiency in growth hormone.

U.S. Pat. No. 6,013,658 discloses peptide derivatives which are usefulin treating disorders resulting from a deficiency in growth hormone.

U.S. Pat. No. 6,022,872 discloses hydroxyethylamino sulfonyl ureacompounds as HIV protease inhibitors.

U.S. Pat. No. 6,060,476 discloses hydroxyethylamino sulfonamidecompounds as HIV protease inhibitors.

International Publication WO 89/01488 discloses renin inhibitingpeptides with a hydroxyethylene or dihydroxyethylene isostere in the10,11-position of the renin substrate angiotensinogen.

International Publication WO92/00750 discloses retroviral proteaseinhibitors.

International Publication WO 94/04492 discloses hydroxyethylamineintermediates useful for the treatment of retroviral diseases such asHIV. This disclosure also presents epoxides as intermediates for theretroviral inhibitors.

International Publication WO 95/06030 discloses epoxides, chloromethylketones, and alcohols prepared as intermediates for HIV proteaseinhibitors, with a single protecting group on the amine and arylalkylside chain substituted with alkyl, nitro, nitrile, alkoxy, andthioalkoxy; a preferred side chain is 4-fluorophenylmethyl.

International Publication WO98/29401 discloses a method for thepreparation of aminoepoxides from aminoaldehydes by which theaminoaldehyde continuously flows into a mixing zone containing an insitu generated halomethyl organometallic reagent.

International Publication WO98/33795 discloses non-peptide inhibitors ofcathepsin D.

International Publication WO98/50342 discloses bis aminomethyl carbonylcompounds as inhibitors of cysteine and serine proteases.

International Publication WO/00/056335 discloses non-peptide inhibitorsof aspartyl proteases. These compounds influence processing of theamyloid precursor protein APP.

EP 0 609 625 discloses HIV protease inhibitors with only one noncyclizednitrogen atom.

Bioorganic & Medicinal Chemistry Letters, 5, 721–726 (1995) describesthe synthesis of compounds useful for the inhibition of HIV protease inwhich the C-terminal nitrogen of the hydroxyethylamine compound isincorporated into a ring system such that a piperidine ring, with anamide substituent next to the nitrogen, is formed.

The hydroxyethylamine “nucleus” or isostere, which is present in thecompounds of the present invention has been employed with success in thearea of HIV protease inhibition. Many of these hydroxyethylaminecompounds are known as well as how to make them. See for example, J. Am.Chem. Soc., 93, 288–291 (1993), Tetrahedron Letters, 28(45) 5569–5572(1987), J. Med. Chem., 38(4), 581–584 (1994), Tetrahedron Letters,38(4), 619–620 (1997).

U.S. Pat. No. 5,648,511 discloses a diprotected aralkyl epoxide.

U.S. Pat. Nos. 5,482,947; 5,508,294; 5,510,349; 5,510,388; 5,521,219;5,610,190; 5,639,769; 5,760,064; and 5,965,588 disclose monoprotected(substituted) aralkyl epoxides.

Tetrahedron Lett., 30(40),5425–5428 (1989) discloses a process in whichdoubly protected alpha-amino aldehydes are transformed into thecorresponding aminoalkyl epoxides.

J. Med. Chem., 36, 2300 (1993) discloses an azide substituted benzylepoxide.

Tetrahedron Lett., 38, 3175 (1997) discloses a process for thepreparation of N-BOC protected epoxides from protected amino acidesters.

J. Med. Chem., 35, 2525 (1992) discloses hydroxyethylamine inhibitors ofHIV protease.

U.S. Pat. No. 5,481,011 discloses arylalkyl amino epoxides in which theamino group is protected by a carbamate functionality.

Synlett, 6, 902 (2000) discloses the preparation of alpha-chloroketonesof aminoprotected-(substituted)benzyl esters.

U.S. Pat. No. 5,648,511 discloses a diprotected aralkyl alcohol.

U.S. Pat. Nos. 5,482,947; 5,508,294; 5,510,349; 5,510,388; 5,521,219;5,610,190; 5,639,769; 5,760,064; and 5,965,588 disclose monoprotected(substituted) aralklyl alcohols.

U.S. Pat. Nos. 5,482,947; 5,508,294; 5,510,349; 5,510,388; 5,521,219;5,610,190; 5,639,769; 5,760,064; and 5,965,588 disclose a process forremoving the protecting group of the monoprotected (substituted)aralklyl alcohols to give the free amino alcohol product as the aminesalt.

U.S. Pat. No. 5,648,511 discloses the removal of the amino protectinggroup of the protected amino-alcohol (VIII) to give the freeamino-alcohol (IX).

U.S. Pat. No. 6,150,344 discloses phosphate containing compounds usefulin treating Alzheimer's disease.

EP 652 009 A1 discloses inhibitors of aspartyl protease which inhibitbeta-amyloid peptide production in cell culture and in vivo. Thecompounds which inhibit intracellular beta-amyloid peptide productionare useful in treating Alzheimer's Disease.

WO00/69262 discloses a new beta-secretase and its use in assays toscreen for potential drug candidates against Alzheimer's disease.

WO01/00663 discloses memapsin 2 (human beta-secretase) as well ascatalytically active recombinant enzyme. In addition, a method ofidentifying inhibitors of memapsin 2, as well as two inhibitors aredisclosed. Both inhibitors that are disclosed are peptides.

WO01/00665 discloses inhibitors of memapsin 2 that are useful intreating Alzheimer's disease.

WO01/19797 discloses lactams of the formula —C—C—CO—N-lactam-W-X-Y-Zwhich are useful in treating Alzheimer's disease.

At present there are no effective treatments for halting, preventing, orreversing the progression of Alzheimer's disease. Therefore, there is anurgent need for pharmaceutical agents capable of slowing the progressionof Alzheimer's disease and/or preventing it in the first place.

Compounds that are effective inhibitors of beta-secretase, that inhibitbeta-secretase-mediated cleavage of APP, that are effective inhibitorsof A beta production, and/or are effective to reduce amyloid betadeposits or plaques, are needed for the treatment and prevention ofdisease characterized by amyloid beta deposits or plaques, such as AD.

SUMMARY OF INVENTION

Disclosed is a substituted amine of formula (X)

where R₁ is:

-   (I) C₁–C₆ alkyl, optionally substituted with one, two or three    substituents selected from the group consisting of C₁–C₃ alkyl,    C₁–C₇ alkyl (optionally substituted with C₁–C₃ alkyl and C₁–C₃    alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy,    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,    —OC═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined    above,-   (II) —CH₂—S(O)₀₋₂—(C₁–C₆ alkyl),-   (III) —CH₂—CH₂—S(O)₀₋₂—(C₁–C₆ alkyl),-   (IV) C₂–C₆ alkenyl with one or two double bonds, optionally    substituted with one, two or three substituents selected from the    group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy,    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,-   (V) C₂–C₆ alkynyl with one or two triple bonds, optionally    substituted with one, two or three substituents selected from the    group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy,    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,-   (VI) —CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero or one and where    R_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl,    dihydronaphthayl, tetralinyl optionally substituted with one, two,    three or four of the following substituents on the aryl ring:    -   (A) C₁–C₆ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁–C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b) where R_(1-a) and        R_(1-b) are as defined above, —C≡N, —CF₃, C₁–C₃ alkoxy,    -   (B) C₂–C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁–C₆ alkyl,    -   (C) C₂–C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁–C₆ alkyl,    -   (D) —F, Cl, —Br and —I,    -   (F) —C₁–C₆ alkoxy optionally substituted with one, two or three        —F,    -   (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined        below,    -   (H) —OH,    -   (I) —C≡N,    -   (J) C₃–C₇ cycloalkyl, optionally substituted with one, two or        three substituents selected from the group consisting of —F,        —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,    -   (K) —CO—(C₁–C₄ alkyl),    -   (L) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (M) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined        above,    -   (N) —SO₂—(C₁–C₄ alkyl),-   (VII) —CH₂)_(n-1)(R_(1-heteroaryl)) where n₁ is as defined above and    where R_(1-heteroaryl) is selected from the group consisting of:    -   pyridinyl,    -   pyrimidinyl,    -   quinolinyl,    -   benzothienyl,    -   indolyl,    -   indolinyl,    -   pryidazinyl,    -   pyrazinyl,    -   isoindolyl,    -   isoquinolyl,    -   quinazolinyl,    -   quinoxalinyl,    -   phthalazinyl,    -   imidazolyl,    -   isoxazolyl,    -   pyrazolyl,    -   oxazolyl,    -   thiazolyl,    -   indolizinyl,    -   indazolyl,    -   benzothiazolyl,    -   benzimidazolyl,    -   benzofuranyl,    -   furanyl,    -   thienyl,    -   pyrrolyl,    -   oxadiazolyl,    -   thiadiazolyl,    -   triazolyl,    -   tetrazolyl,    -   oxazolopyridinyl,    -   imidazopyridinyl,    -   isothiazolyl,    -   naphthyridinyl,    -   cinnolinyl,    -   carbazolyl,    -   beta-carbolinyl,    -   isochromanyl,    -   chromanyl,    -   tetrahydroisoquinolinyl,    -   isoindolinyl,    -   isobenzotetrahydrofuranyl,    -   isobenzotetrahydrothienyl,    -   isobenzothienyl,    -   benzoxazolyl,    -   pyridopyridinyl,    -   benzotetrahydrofuranyl,    -   benzotetrahydrothienyl,    -   purinyl,    -   benzodioxolyl,    -   triazinyl,    -   phenoxazinyl,    -   phenothiazinyl,    -   pteridinyl,    -   benzothiazolyl,    -   imidazopyridinyl,    -   imidazothiazolyl,    -   dihydrobenzisoxazinyl,    -   benzisoxazinyl,    -   benzoxazinyl,    -   dihydrobenzisothiazinyl,    -   benzopyranyl,    -   benzothiopyranyl,    -   coumarinyl,    -   isocoumarinyl,    -   chromonyl,    -   chromanonyl,    -   pyridinyl-N-oxide    -   tetrahydroquinolinyl    -   dihydroquinolinyl    -   dihydroquinolinonyl    -   dihydroisoquinolinonyl    -   dihydrocoumarinyl    -   dihydroisocoumarinyl    -   isoindolinonyl    -   benzodioxanyl    -   benzoxazolinonyl    -   pyrrolyl N-oxide,    -   pyrimidinyl N-oxide,    -   pyridazinyl N-oxide,    -   pyrazinyl N-oxide,    -   quinolinyl N-oxide,    -   indolyl N-oxide,    -   indolinyl N-oxide,    -   isoquinolyl N-oxide,    -   quinazolinyl N-oxide,    -   quinoxalinyl N-oxide,    -   phthalazinyl N-oxide,    -   imidazolyl N-oxide,    -   isoxazolyl N-oxide,    -   oxazolyl N-oxide,    -   thiazolyl N-oxide,    -   indolizinyl N-oxide,    -   indazolyl N-oxide,    -   benzothiazolyl N-oxide,    -   benzimidazolyl N-oxide,    -   pyrrolyl N-oxide,    -   oxadiazolyl N-oxide,    -   thiadiazolyl N-oxide,    -   triazolyl N-oxide,    -   tetrazolyl N-oxide,    -   benzothiopyranyl S-oxide,    -   benzothiopyranyl S,S-dioxide,    -    where the R_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by        any ring atom of the parent R_(N-heteroaryl) group substituted        by hydrogen such that the new bond to the R_(1-heteroaryl) group        replaces the hydrogen atom and its bond, where heteroaryl is        optionally substituted with one, two, three or four of:        -   (1) C₁–C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃,            C₁–C₃ alkoxy,        -   (2) C₂–C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁–C₆ alkyl,        -   (3) C₂–C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁–C₆ alkyl,        -   (4) —F, —Cl, —Br and —I,        -   (6) —C₁–C₆ alkoxy optionally substituted with one, two, or            three —F,        -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined below,        -   (8) —OH,        -   (9) —C≡N,        -   (10) C₃–C₇ cycloalkyl, optionally substituted with one, two            or three substituents selected from the group consisting of            —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy,            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆            alkyl,        -   (11) —CO—(C₁–C₄ alkyl),        -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (14) —SO₂—(C₁–C₄ alkyl), with the proviso that when n₁ is            zero R_(1-heteroaryl) is not bonded to the carbon chain by            nitrogen,-   (VIII) —(CH₂)_(n-1)—(R_(1-heterocycle)) where n₁ is as defined above    and R_(1-heterocycle) is selected from the group consisting of:    -   morpholinyl,    -   thiomorpholinyl,    -   thiomorpholinyl S-oxide,    -   thiomorpholinyl S,S-dioxide,    -   piperazinyl,    -   homopiperazinyl,    -   pyrrolidinyl,    -   pyrrolinyl,    -   tetrahydropyranyl,    -   piperidinyl,    -   tetrahydrofuranyl,    -   tetrahydrothienyl,    -   homopiperidinyl,    -   homomorpholinyl,    -   homothiomorpholinyl,    -   homothiomorpholinyl S,S-dioxide, and    -   oxazolidinonyl,    -   dihydropyrazolyl    -   dihydropyrrolyl    -   dihydropyrazinyl    -   dihydropyridinyl    -   dihydropyrimidinyl    -   dihydrofuryl    -   dihydropyranyl    -   tetrahydrothienyl S-oxide    -   tetrahydrothienyl S,S-dioxide    -   homothiomorpholinyl S-oxide    -    where the R_(1-heterocycle) group is bonded by any atom of the        parent R_(1-heterocycle) group substituted by hydrogen such that        the new bond to the R_(1-heterocycle) group replaces the        hydrogen atom and its bond, where heterocycle is optionally        substituted with one, two, three or four:        -   (1) C₁–C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃,            C₁–C₃ alkoxy,        -   (2) C₂–C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁–C₆ alkyl,        -   (3) C₂–C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁–C₃ alkoxy, —NR_(1-a)R_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are —H or C₁–C₆ alkyl,        -   (4) —F, —Cl, —Br and —I,        -   (5) C₁–C₆ alkoxy,        -   (6) —C₁–C₆ alkoxy optionally substituted with one, two, or            three —F,        -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined below,        -   (8) —OH,        -   (9) —C≡N,        -   (10) C₃–C₇ cycloalkyl, optionally substituted with one, two            or three substituents selected from the group consisting of            —F, —Cl, —OH, —SH —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,        -   (11) —CO—(C₁–C₄ alkyl),        -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (14) —SO₂—(C₁–C₄ alkyl),        -   (15) ═O, with the proviso that when n₁ is zero            R_(1-heterocycle) is not bonded to the carbon chain by            nitrogen;            where R₂ is selected from the group consisting of:-   (I)-H,-   (II) C₁–C₆ alkyl, optionally substituted with one, two or three    substituents selected from the group consisting of C₁–C₃ alkyl, —F,    —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b)    where R_(1-a) and R_(1-b) are as defined above,-   (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or R_(1-heteroaryl)    where R_(1-aryl) and R_(1-heteroaryl) are as defined above;-   (IV) C₂–C₆ alkenyl with one or two double bonds, optionally    substituted with one, two or three substituents selected from the    group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy,    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,-   (V) C₂–C₆ alkynyl with one or two triple bonds, optionally    substituted with one, two or three substituents selected from the    group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy,    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,-   (VI) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionally substituted with one,    two or three substituents selected from the group consisting of —F,    —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where    R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,    where R₃ is selected from the group consisting of:-   (I)-H,-   (II) C₁–C₆ alkyl, optionally substituted with one, two or three    substituents selected from the group consisting of C₁–C₃ alkyl, —F,    —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b)    where R_(1-a) and R_(1-b) are as defined above,-   (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or R_(1-heteroaryl)    where R_(1-aryl) and R_(1-heteroaryl) are as defined above;-   (IV) C₂–C₆ alkenyl with one or two double bonds,-   (V) C₂–C₆ alkynyl with one or two triple bonds,-   (VI) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionally substituted with one,    two or three substituents selected from the group consisting of —F,    —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where    R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, and where R₂ and R₃ are    taken together with the carbon to which they are attached to form a    carbocycle of three, four, five, six, and seven carbon atoms,    optionally where one carbon atom is replaced by a heteroatom    selected from the group consisting of —O—, —S—, —SO₂—, —NR_(N-2)—,    where R_(N-2) is as defined below;    where R_(N) is:-   (I) R_(N-1)—X_(N)— where X_(N) is selected from the group consisting    of:    -   (A) —CO—,    -   (B) —SO₂—,    -   (C) —(CR′R″)₁₋₆ where R′ and R″ are the same or different and        are —H and C₁–C₄ alkyl,    -   (D) —CO—(CR′R″)₁₋₆—X_(N-1) where X_(N-1) is selected from the        group consisting of —O—, —S— and —NR′— and where R′ and R″ are        as defined above,    -   (E) a single bond;        where R_(N-1) is selected from the group consisting of:    -   (A) R_(N-aryl) where R_(N-aryl) is phenyl, 1-naphthyl,        2-naphthyl, tetralinyl, indanyl, dihydronaphthyl or        6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, optionally        substituted with one, two or three of the following substituents        which can be the same or different and are:        -   (1) C₁–C₆ alkyl, optionally substituted with one, two or            three substituents selected from the group consisting of            C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃            alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (2) —OH,        -   (3) —NO₂,        -   (4) —F, —Cl, —Br, —I,        -   (5) —CO—OH,        -   (6) —C≡N,        -   (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3)            are the same or different and are selected from the group            consisting of:            -   (a) —H,            -   (b) —C₁–C₆ alkyl optionally substituted with one                substitutent selected from the group consisting of:                -   (i) —OH,                -   (ii) —NH₂,            -   (c) —C₁–C₆ alkyl optionally substituted with one to                three —F, —Cl, —Br, —I,            -   (d) —C₃–C₇ cycloalkyl,            -   (e) —(C₁–C₂ alkyl)—(C₃–C₇ cycloalkyl),            -   (f) —(C₁–C₆ alkyl)—O—(C₁–C₃ alkyl),            -   (g) —C₂–C₆ alkenyl with one or two double bonds,            -   (h) —C₂–C₆ alkynyl with one or two triple bonds,            -   (i) —C₁–C₆ alkyl chain with one double bond and one                triple bond,            -   (j) —R_(1-aryl) where R_(1-aryl) is as defined above,            -   (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as                defined above,        -   (8) —(CH₂)₀₋₄—CO—(C₁–C₁₂ alkyl),        -   (9) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkenyl with one, two or three            double bonds),        -   (10) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkynyl with one, two or three            triple bonds),        -   (11) —(CH₂)₀₋₄—CO—(C₃–C₇ cycloalkyl),        -   (12) —(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as defined            above,        -   (13) —CH₂)₀₋₄—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is            as defined above,        -   (14) —CH₂)₀₋₄—CO—R_(1-heterocycle) where R_(1-heterocycle)            is as defined above,        -   (15) —CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from the            group consisting of morpholinyl, thiomorpholinyl,            piperazinyl, piperidinyl, homomorpholinyl,            homothiomorpholinyl, homothiomorpholinyl S-oxide,            homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl            where each group is optionally substituted with one, two,            three, or four of C₁–C₆ alkyl,        -   (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from            the group consisting of:            -   (a) C₁–C₆ alkyl,            -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as                defined above,            -   (c) C₂–C₆ alkenyl containing one or two double bonds,            -   (d) C₂–C₆ alkynyl containing one or two triple bonds,            -   (e) C₃–C₇ cycloalkyl,            -   (f) —CH₂)₀₋₂—(R_(1-heteroaryl)) where R_(1-heteroaryl)                is as defined above,        -   (17) —CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3)            are as defined above,        -   (18) —(CH₂)₀₋₄—SO—(C₁–C₈ alkyl),        -   (19) —(CH₂)₀₋₄—SO₂—(C₁–C₁₂ alkyl),        -   (20) —(CH₂)₀₋₄—SO₂—(C₃–C₇ cycloalkyl),        -   (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5)            can be the same or different and is as defined above,        -   (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, where R_(N-5)            can be the same or different and is as defined above,        -   (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be the            same or different and is as defined above,        -   (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) where R_(N-5) and            R_(N-2) can be the same or different and are as defined            above,        -   (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can            be the same or different and are as defined above,        -   (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above,        -   (27) —(CH₂)₀₋₄—O—CO—(C₁–C₆ alkyl),        -   (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1) is            —H or C₁–C₄ alkyl,        -   (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (30) —(CH₂)₀₋₄—CS—N(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (31) —CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) is as defined            above,        -   (33) —(CH₂)₀₋₄—S—(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (34) —(CH₂)₀₋₄—O—(C₁–C₆ alkyl optionally substituted with            one, two, three, four, or five of —F),        -   (35) C₃–C₇ cycloalkyl,        -   (36) C₂–C₆ alkenyl with one or two double bonds optionally            substituted with C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,            —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (37) C₂–C₆ alkynyl with one or two triple bonds optionally            substituted with C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,            —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5)            and R_(N-2) can be the same or different and are as            described above,        -   (39) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl,    -   (B) —R_(N-heteroaryl) where R_(N-heteroaryl) is selected from        the group consisting of:        -   pyridinyl,        -   pyrimidinyl,        -   quinolinyl,        -   benzothienyl,        -   indolyl,        -   indolinyl,        -   pryidazinyl,        -   pyrazinyl,        -   isoindolyl,        -   isoquinolyl,        -   quinazolinyl,        -   quinoxalinyl,        -   phthalazinyl,        -   imidazolyl,        -   isoxazolyl,        -   pyrazolyl,        -   oxazolyl,        -   thiazolyl,        -   indolizinyl,        -   indazolyl,        -   benzothiazolyl,        -   benzimidazolyl,        -   benzofuranyl,        -   furanyl,        -   thienyl,        -   pyrrolyl,        -   oxadiazolyl,        -   thiadiazolyl,        -   triazolyl,        -   tetrazolyl,        -   oxazolopyridinyl,        -   imidazopyridinyl,        -   isothiazolyl,        -   naphthyridinyl,        -   cinnolinyl,        -   carbazolyl,        -   beta-carbolinyl,        -   isochromanyl,        -   chromanyl,        -   tetrahydroisoquinolinyl,        -   isoindolinyl,        -   isobenzotetrahydrofuranyl,        -   isobenzotetrahydrothienyl,        -   isobenzothienyl,        -   benzoxazolyl,        -   pyridopyridinyl,        -   benzotetrahydrofuranyl,        -   benzotetrahydrothienyl,        -   purinyl,        -   benzodioxolyl,        -   triazinyl,        -   henoxazinyl,        -   phenothiazinyl,        -   pteridinyl,        -   benzothiazolyl,        -   imidazopyridinyl,        -   imidazothiazolyl,        -   dihydrobenzisoxazinyl,        -   benzisoxazinyl,        -   benzoxazinyl,        -   dihydrobenzisothiazinyl,        -   benzopyranyl,        -   benzothiopyranyl,        -   coumarinyl,        -   isocoumarinyl,        -   chromonyl,        -   chromanonyl,        -   pyridinyl-N-oxide,        -   tetrahydroquinolinyl        -   dihydroquinolinyl        -   dihydroquinolinonyl        -   dihydroisoquinolinonyl        -   dihydrocoumarinyl        -   dihydroisocoumarinyl        -   isoindolinonyl        -   benzodioxanyl        -   benzoxazolinonyl        -   pyrrolyl N-oxide,        -   pyrimidinyl N-oxide,        -   pyridazinyl N-oxide,        -   pyrazinyl N-oxide,        -   quinolinyl N-oxide,        -   indolyl N-oxide,        -   indolinyl N-oxide,        -   isoquinolyl N-oxide,        -   quinazolinyl N-oxide,        -   quinoxalinyl N-oxide,        -   phthalazinyl N-oxide,        -   imidazolyl N-oxide,        -   isoxazolyl N-oxide,        -   oxazolyl N-oxide,        -   thiazolyl N-oxide,        -   indolizinyl N-oxide,        -   indazolyl N-oxide,        -   benzothiazolyl N-oxide,        -   benzimidazolyl N-oxide,        -   pyrrolyl N-oxide,        -   oxadiazolyl N-oxide,        -   thiadiazolyl N-oxide,        -   triazolyl N-oxide,        -   tetrazolyl N-oxide,        -   benzothiopyranyl S-oxide ,        -   benzothiopyranyl S,S-dioxide,    -    where the R_(N-heteroaryl) group is bonded by any atom of the        parent R_(N-heteroaryl) group substituted by hydrogen such that        the new bond to the R_(N-heteroaryl) group replaces the hydrogen        atom and its bond, where heteroaryl is optionally substituted        with one, two, three, or four of:        -   (1) C₁–C₆ alkyl, optionally substituted with one, two or            three substituents selected from the group consisting Of            C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃            alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (2) —OH,        -   (3) —NO₂,        -   (4) —F, —Cl, —Br, —I,        -   (5) —CO—OH,        -   (6) —C≡N,        -   (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3)            are the same or different and are selected from the group            consisting of:            -   (a) —H,            -   (b) —C₁–C₆ alkyl optionally substituted with one                substitutent selected from the group consisting of:                -   (i) —OH,                -   (ii) —NH₂,            -   (c) —C₁–C₆ alkyl optionally substituted with one to                three —F, —Cl, —Br, —I,            -   (d) —C₃–C₇ cycloalkyl,            -   (e) —(C₁–C₂ alkyl)—(C₃–C₇ cycloalkyl),            -   (f) —(C₁–C₆ alkyl)—O—(C₁–C₃ alkyl),            -   (g) —C₂–C₆ alkenyl with one or two double bonds,            -   (h) —C₂–C₆ alkynyl with one or two triple bonds,            -   (i) —C₁–C₆ alkyl chain with one double bond and one                triple bond,            -   (j) —R_(1-aryl) where R_(1-aryl) is as defined above,            -   (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as                defined above,        -   (8) —(CH₂)₀₋₄—CO—(C₁–C₁₂ alkyl),        -   (9) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkenyl with one, two or three            double bonds),        -   (10) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkynyl with one, two or three            triple bonds),        -   (11) —(CH₂)₀₋₄—CO—(C₃–C₇ cycloalkyl),        -   (12) —(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as defined            above,        -   (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is            as defined above,        -   (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) where R_(1-heterocycle)            is as defined above,        -   (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from the            group consisting of morpholinyl, thiomorpholinyl,            piperazinyl, piperidinyl, homomorpholinyl,            homothiomorpholinyl, homothiomorpholinyl S-oxide,            homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl            where each group is optionally substituted with one, two,            three, or four of C₁–C₆ alkyl,        -   (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from            the group consisting of:            -   (a) C₁–C₆ alkyl,            -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as                defined above,            -   (c) C₂–C₆ alkenyl containing one or two double bonds,            -   (d) C₂–C₆ alkynyl containing one or two triple bonds,            -   (e) C₃–C₇ cycloalkyl,            -   (f) —CH₂)₀₋₂—(R_(1-heteroaryl)) where R_(1-heteroaryl)                is as defined above,        -   (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3)            are as defined above,        -   (18) —(CH₂)₀₋₄—SO—(C₁–C₈ alkyl),        -   (19) —(CH₂)₀₋₄—SO₂—(C₁–C₁₂ alkyl),        -   (20) —(CH₂)₀₋₄—SO₂—(C₃–C₇ cycloalkyl),        -   (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5)            can be the same or different and is as defined above,        -   (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, where R_(N-5)            can be the same or different and is as defined above,        -   (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be the            same or different and is as defined above,        -   (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) where R_(N-5) and            R_(N-2) can be the same or different and are as defined            above,        -   (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can            be the same or different and are as defined above,        -   (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above,        -   (27) —(CH₂)₀₋₄—O—CO—(C₁–C₆ alkyl),        -   (28) —(CH₂)₀₋₄—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1) is            —H or C₁–C₄ alkyl,        -   (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (31) —CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) is as defined            above,        -   (33) —(CH₂)₀₋₄—S—(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (34) —(CH₂)₀₋₄—O—(C₁–C₆ alkyl optionally substituted with            one, two, three, four, or five of —F),        -   (35) C₃–C₇ cycloalkyl,        -   (36) C₂–C₆ alkenyl with one or two double bonds optionally            substituted with C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,            —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (37) C₂–C₆ alkynyl with one or two triple bonds optionally            substituted with C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,            —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5)            and R_(N-2) can be the same or different and are as            described above,        -   (39) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl,    -   (C) R_(N-aryl)—W—R_(N-aryl),    -   (D) R_(N-aryl)—W—R_(N-heteroaryl),    -   (E) R_(N-aryl)—W—R_(N-1-heterocycle), where R_(N-heterocycle) is        defined as R_(1-heterocycle) is defined above,    -   (F) R_(N-heteroaryl)—W—R_(N-aryl),    -   (G) R_(N-heteroaryl)—W—R_(N-heteroaryl),    -   (H) R_(N-heteroaryl)—W—R_(N-1-heterocycle), where        R_(N-1-heterocycle) is defined as R_(1-heterocycle) is defined        above,    -   (I) R_(N-heterocycle)—W—R_(N-aryl),    -   (J) R_(N-heterocycle)—W—R_(N-heteroaryl),    -   (K) R_(N-heterocycle)—W—R_(N-1-heterocycle),    -    where W is        -   (1) —(CH₂)₀₋₄—,        -   (2) —O—,        -   (3) —S(O)₀₋₂—,        -   (4) —N(R_(N-5))— where R_(N-5) is as defined above, or        -   (5) —CO—;-   (II) —CO—(C₁–C₁₀ alkyl) where alkyl is optionally substituted with    one two or three substitutents selected from the group consisting    of:    -   (A) —OH,    -   (B) —C₁–C₆ alkoxy,    -   (C) —C₁–C₆ thioalkoxy,    -   (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁–C₆ alkyl or -phenyl,    -   (E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (F) —CO—RN₄ where R_(N-4) is as defined above,    -   (G) —SO₂—(C₁–C₈ alkyl),    -   (H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (I) —NH—CO—(C₁–C₆ alkyl),    -   (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or        different and are as defined above,    -   (L) —R_(N-4) where R_(N-4) is as defined above,    -   (M) —O—CO—(C₁–C₆ alkyl),    -   (N) —O—CO—NR_(N-8)R_(N-8) where R_(N-8) are the same or        different and are as defined above,    -   (O) —O—(C₁–C₅ alkyl)—COOH,    -   (P) —O—(C₁–C₆ alkyl optionally substituted with one, two, or        three of —F, —CI, —Br, —I),    -   (Q) —NH—SO₂—(C₁–C₆ alkyl),    -   (R) —F, —Cl,-   (III) —CO—(C₁–C₆ alkyl)—O—(C₁–C₆ alkyl) where alkyl is optionally    substituted with one, two, or three substitutents selected from the    group consisting of:    -   (A) —OH,    -   (B) —C₁–C₆ alkoxy,    -   (C) —C₁–C₆ thioalkoxy,    -   (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁–C₆ alkyl or -phenyl,    -   (E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (F) —CO—R_(N-4) where R_(N-4) is as defined above,    -   (G) —SO₂—(C₁-C8 alkyl),    -   (H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (I) —NH—CO—(C₁–C₆ alkyl),    -   (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or        different and are as defined above,    -   (L) —R_(N-4) where R_(N-4) is as defined above,    -   (M) —O—CO—(C₁–C₆ alkyl),    -   (N) —O—CO—NR_(N-8)R_(N-8) where R_(N-8) are the same or        different and are as defined above,    -   (O) —O—(C₁–C₅ alkyl)—COOH,    -   (P) —O—(C₁–C₆ alkyl optionally substituted with one, two, or        three of —F, —CI, —Br, —I),    -   (Q) —NH—SO₂—(C₁–C₆ alkyl),    -   (R) —F, —Cl,-   (IV) —CO—(C₁–C₆ alkyl)—S—(C₁–C₆ alkyl) where alkyl is optionally    substituted with one, two, or three of substitutents selected from    the group consisting of:    -   (A) —OH,    -   (B) —C₁–C₆ alkoxy,    -   (C) —C₁–C₆ thioalkoxy,    -   (D) —CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (F) —CO—R_(N-4) where R_(N-4) is as defined above,    -   (G) —SO₂—(C₁–C₈ alkyl),    -   (H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (I) —NH—CO—(C₁–C₆ alkyl),    -   (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or        different and are as defined above,    -   (L) —R_(N-4) where R_(N-4) is as defined above,    -   (M) —O—CO—(C₁–C₆ alkyl),    -   (N) —O—CO—NR_(N-8)R_(N-8) where the RN8s are the same or        different and are as defined above,    -   (O) —O—(C₁–C₅ alkyl)—COOH,    -   (P) —O—(C₁–C₆ alkyl optionally substituted with one, two, or        three of —F, —Cl, —Br, —I),    -   (Q) —NH—SO₂—(C₁–C₆ alkyl),    -   (R) —F, —Cl,-   (V)    —CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl))    where R_(N-aryl) and R_(N-heteroaryl) are as defined above, where    R_(N-10) is selected from the group consisting of:    -   (A) —H,    -   (B) C₁–C₆ alkyl,    -   (C) C₃–C₇ cycloalkyl,    -   (D) C₂–C₆ alkenyl with one double bond,    -   (E) C₂–C₆ alkynyl with one triple bond,    -   (F) R_(1-aryl) where R_(1-aryl) is as defined above,    -   (G) R_(N-heteroaryl) where R_(N-heteroaryl) is as defined above,-   (VI) —CO—(C₃–C₈ cycloalkyl) where alkyl is optionally substituted    with one or two substitutents selected from the group consisting of:    -   (A) —(CH₂)₀₋₄—OH,    -   (B) —(CH₂)₀₋₄–C₁–C₆ alkoxy,    -   (C) —(CH₂)₀₋₄–C₁–C₆ thioalkoxy,    -   (D) —(CH₂)₀₋₄—CO—O—R_(N-8) where R_(N-8) is —H, C₁–C₆ alkyl or        -phenyl,    -   (E) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are        the same or different and are as defined above,    -   (F) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is as defined above,    -   (G) —(CH₂)₀₋₄—SO₂—(C₁–C₈ alkyl),    -   (H) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are        the same or different and are as defined above,    -   (I) —(CH₂)₀₋₄—NH—CO—(C₁–C₆ alkyl),    -   (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (K) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the        same or different and are as defined above,    -   (L) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above,    -   (M) —O—CO—(C₁–C₆ alkyl),    -   (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8)s are the same or        different and are as defined above,    -   (O) —O—(C₁–C₅ alkyl)—COOH,    -   (P) —O—(C₁–C₆ alkyl optionally substituted with one, two, or        three of —F, —Cl, —Br, —I),    -   (Q) —NH—SO₂—(C₁–C₆ alkyl),    -   (R) —F, —Cl,        where R_(C) is:-   (I) —C₁–C₁₀ alkyl optionally substituted with one, two or three    substituents selected from the group consisting of C₁–C₃ alkyl, —F,    —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl,    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    —OC═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined    above, —S(═O)₀₋₂ R_(1-a) where R_(1-a) is as defined above,    —NR_(1-a)C═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as    defined above, —C═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as    defined above, and —S(═O)₂ NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)    are as defined above,-   (II) —(CH₂)₀₋₃—(C₃–C₈) cycloalkyl where cycloalkyl can be optionally    substituted with one, two or three substituents selected from the    group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,    —CF₃, C₁–C₆ alkoxy, —O-phenyl, —CO—OH, —CO-O—(C₁–C₄ alkyl),    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,-   (III) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) where R_(C-x) and R_(C-y) are    -    —H,    -    C₁–C₄ alkyl optionally substituted with one or two —OH,    -    C₁–C₄ alkoxy optionally substituted with one, two, or three of        —F,    -    —(CH₂)₀₋₄–C₃–C₇ cycloalkyl,    -    C₂–C₆ alkenyl containing one or two double bonds,    -    C₂–C₆ alkynyl containing one or two triple bonds,    -    phenyl,        and where R_(C-x) and R_(C-y) are taken together with the carbon        to which they are attached to form a carbocycle of three, four,        five, six and seven carbon atoms, optionally where one carbon        atom is replaced by a heteroatom selected from the group        consisting of —O—, —S—, —SO₂—, —NR_(N-2)— and R_(C-aryl) is        defined as R_(N-aryl) is defined above;-   (IV) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl) where R_(C-heteroaryl)    is defined as R_(N-heteroaryl) is defined above and R_(C-x) and    R_(C-y) are as defined above,-   (V) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-aryl) where R_(C-aryl),    R_(C-x) and R_(C-y) are as defined above,-   (VI) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-heteroaryl) where    R_(C-aryl), R_(C-heteroaryl), R_(C-x) and R_(C-y) are as defined    above,-   (VII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-aryl) where    R_(C-heteroaryl), R_(C-aryl), R_(C-x) and R_(C-y) are as defined    above,-   (VIII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-heteroaryl) where    R_(C-heteroaryl), R_(C-x) and R_(C-y) are as defined above,-   (IX) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-heterocycle) where    R_(C-aryl), R_(C-x) and R_(C-y) are as defined above, and    R_(C-heterocycle) is defined as R_(N-heterocycle) is defined above,-   (X) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-heterocycle) where    R_(C-heteroaryl), R_(C-heterocycle), R_(C-x) and R_(C-y) are as    defined above,-   (XI) —(CR_(C-x)R_(C-y))₀₋₄R_(C-heterocycle)—R_(C-aryl) where    R_(C-heterocycle), R_(C-aryl), R_(C-x) and R_(C-y) are as defined    above,-   (XII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-heteroaryl) where    R_(C-heterocycle), R_(C-heteroaryl), R_(C-x) and R_(C-y) are as    defined above,-   (XIII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-heterocycle)    where R_(C-heterocycle), R_(C-x) and R_(C-y) are as defined above,-   (XIV) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle) where    R_(C-heterocycle), R_(C-x) and R_(C-y) are as defined above,-   (XV) —[C(R_(C-1))(R_(C-2))]₁₋₃—CO—N—(R_(C-3))₂ where R_(C-1) and    R_(C-2) are the same or different and are selected from the group    consisting of:    -   (A) —H,    -   (B) —C₁–C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁–C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (C) C₂–C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (D) C₂–C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (E) —(CH₂)₁₋₂—S(O)₀₋₂—(C₁–C₆ alkyl),    -   (F) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionally substituted with one,        two or three substituents selected from the group consisting of        C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆        alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)        are as defined above,    -   (G) —(C₁–C₄ alkyl)—R_(C′-aryl) where R_(C′-aryl) is as defined        for R_(1-aryl),    -   (H) —(C₁–C₄ alkyl)—R_(C-heteroaryl) where R_(C-heteroaryl) is as        defined above,    -   (I) —(C₁–C₄ alkyl)—R_(C-heterocycle) where R_(C-heterocycle) is        as defined above,    -   (J) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined        above,    -   (K) —R_(C-heterocycle) where R_(C-heterocycle) is as defined        above,    -   (M) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₀₋₄—R_(C′-aryl) where R_(C-4) is —O—,        -S— or —NR_(C-5)— where R_(C-5) is C₁–C₆ alkyl, and where        R_(C′-aryl) is defined above,    -   (N) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₀₋₄—R_(C-heteroaryl) where R_(C-4)        and R_(C-heteroaryl) are as defined above,    -   (O) —R_(C′-aryl) where R_(C′-aryl) is as defined above,        and where R_(C-3) is the same or different and is:    -   (A) —H,    -   (B) —C₁–C₆ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁–C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (C) C₂–C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (D) C₂–C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (E) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionally substituted with one,        two or three substituents selected from the group consisting of        C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆        alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)        are as defined above,    -   (F) —R_(C′-aryl) where R_(C′-aryl) is as defined above,    -   (G) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined        above,    -   (H) —R_(C-heterocycle) where R_(C-heterocycle) is as defined        above,    -   (I) —(C₁–C₄ alkyl)—R_(C′-aryl) where R_(C′-aryl) is as defined        above,    -   (J) —(C₁–C₄ alkyl)—R_(C-heteroaryl) where R_(C-heteroaryl) is as        defined above,    -   (K) —(C₁–C₄ alkyl)—R_(C-heterocycle) where R_(C-heterocycle) is        as defined above,-   (XVI) —CH(R_(C-aryl))₂ where R_(C-aryl) are the same or different    and are as defined above,-   (XVII) —CH(R_(C-heteroaryl))₂ where R_(C-heteroaryl) are the same or    different and are as defined above,-   (XVIII) —CH(R_(C-aryl))(R_(C-heteroaryl)) where R_(C-aryl) and    R_(C-heteroaryl) are as defined above,-   (XIX) -cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to    R_(C-aryl) or R_(C-heteroaryl) or R_(C-heterocycle) where R_(C-aryl)    or R_(C-heteroaryl) or R_(C-heterocycle) are as defined above where    one carbon of cyclopentyl, cyclohexyl, or -cycloheptyl is optionally    replaced with NH, NR_(N-5), O, S(═O)₀₋₂, and where cyclopentyl,    cyclohexyl, or -cycloheptyl can be optionally substituted with one    or two —C₁–C₃ alkyl, —F, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, ═O,    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,-   (XX) C₂–C₁₀ alkenyl containing one or two double bonds optionally    substituted with one, two or three substituents selected from the    group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,    —CF₃, C₁–C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and    R_(1-b) are as defined above,-   (XXI) C₂–C₁₀ alkynyl containing one or two triple bonds optionally    substituted with one, two or three substituents selected from the    group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,    —CF₃, C₁–C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and    R_(1-b) are as defined above,-   (XXI) —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁—R_(C-aryl) where R_(C-aryl) is as    defined above and R_(C-6) is —(CH₂)₀₋₆—OH,-   (XXII) —(CH₂)₀₋₁—CHR_(C-6)—CH₂)₀₋₁—R_(C-heteroaryl) where    R_(C-heteroaryl) and R_(C-6) is as defined above,-   (XXIII) —CH(—R_(C-aryl) or R_(C-heteroaryl))—CO—O(C₁–C₄ alkyl) where    R_(C-aryl) and R_(C-heteroaryl) are as defined above,-   (XXIV) —CH(—CH₂—OH)—CH(—OH)-micro-NO₂,-   (XXV) (C₁–C₆ alkyl)—O—(C₁–C₆ alkyl)—OH,-   (XXVII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,-   (XXVIII) —H,-   (XXIX) —(CH₂)₀₋₆—C(═NR_(1-a))(NR_(1-a)R_(1-b)) where R_(1-a) and    R_(1-b) are as defined above, and pharmaceutically acceptable salts    thereof.

Also disclosed is a substituted amine of the formula (X′)

-   where R₁, R₂, R₃ and R_(C) are as defined above;-   where Ring A is phenyl, 1-naphthyl and 2-naphthyl optionally    substituted with one, two or three of the following substituents    which can be the same or different and are:    -   (1) C₁–C₆ alkyl,    -   (2) —F, —Cl, —Br, I,    -   (3) —OH,    -   (4) —NO₂,    -   (5) —CO—OH,    -   (6) —C≡N,    -   (7) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined        above,    -   (8) —CO—(C₃–C₁₂ alkyl),    -   (9) —CO—(C₃–C₆ cycloalkyl),    -   (10) —CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as defined        in above,    -   (11) —CO—R_(1-heterocycle) where R_(1-heterocycle) is as defined        in above,    -   (12) —CO—R_(N-4) where R_(N-4) is as defined in above,    -   (13) —CO—O—R_(N-5) where R_(N-5) is as defined in above,    -   (14) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as        defined above,    -   (15) —SO—(C₁–C₈ alkyl),    -   (16) —SO₂—(C₃–C₁₂ alkyl) with the proviso that the alkyl group        not be straight chained,    -   (17) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,    -   (18) —NH—CO—N(C₁–C₃ alkyl)₂,    -   (19) —N—CS—N(C₁–C₃ alkyl)₂,    -   (20) —N(—H or C₁–C₃ alkyl)—CO—R_(N-5) where R_(N-5) is as        defined above,    -   (21) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can be the same        or different and are as defined above,    -   (22) —R_(N-4) where R_(N-4) is as defined above,    -   (23) —O—CO—(C₁–C₆ alkyl),    -   (24) —O—CO—N(C₁–C₃ alkyl)₂,    -   (25) —O—CS—N(C₁–C₃ alkyl)₂,    -   (26) —O—(C₁–C₆ alkyl),    -   (27) —O—(C₂–C₅ alkyl)—COOH,    -   (28) —S—(C₁–C₆ alkyl) and pharmaceutically acceptable salts        thereof.

Additionally disclosed is a protected compound of the formula (III)

where R₁, R₂ and R₃ are as defined above;

where X₁ is —Cl, —Br, —I, —O-tosylate, —O-mesylate, —O-nosylate;

where PROTECTING GROUP is selected from the group consisting oft-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, acetyl,trichloroacetyl, dichloroacetyl, chloroacetyl, trifluoroacetyl,difluoroacetyl, fluoroacetyl, 4-phenylbenzyloxycarbonyl,2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycabonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl,fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobornyloxycarbonyl and 1-piperidyloxycarbonyl, 9-fluorenylmethylcarbonate, —CH—CH═CH₂ and phenyl-C(═N—)—H.

Further disclosed is an alcohol of the formula (IV)

where R₁, R₂, R₃, X₁ and PROTECTING GROUP are as defined above.

Additionally disclosed is an epoxide of the formula (V)

where R₂, R₃ and PROTECTING GROUP are as defined above and where R₁ is:

-   -   —CH₂-phenyl where -phenyl is substituted with two —F,    -   —(CH₂)_(n1)—R_(1-heteroaryl) where R_(1-heteroaryl) is as        defined above, and    -   —(CH₂)_(n1)—R_(1-heterocycle) where R_(1-heterocycle) is as        defined above.

Further disclosed is a protected alcohol of the formula (VII)

where R₂, R₃, R_(C) and PROTECTING GROUP are as defined above, and whereR₁ is:

-   -   —(CH₂-phenyl where -phenyl is substituted with two —F,    -   —(CH₂)_(n1)—R_(1-heteroaryl) where R_(1-heteroaryl) is as        defined above and    -   —(CH₂)_(n1)—R_(1-heterocycle) where R_(1-heterocycle) is as        defined above and chemically acceptable salts thereof.

Also disclosed is an amine of the formula (VIII)

where R₂, R₃ and R_(C) are as defined above and where R₁ is:

-   -   —(CH₂-phenyl where -phenyl is substituted with two —F,    -   —(CH₂)_(n1)—R_(1-heteroaryl) where R_(1-heteroaryl) is as        defined above and    -   —(CH₂)_(n1)—R_(1-heterocycle) where R_(1-heterocycle) is as        defined above and chemically acceptable salts thereof.

Disclosed is a protected ketone of formula (XI)

where R₂, R₃, R_(C) and PROTECTING GROUP are as defined above and whereR₁ is:

-   -   —CH₂-phenyl where -phenyl is substituted with two —F,    -   —(CH₂)_(n1)—R_(1-heteroaryl) where R_(1-heteroaryl) is as        defined above and    -   —(CH₂)_(n1)—R_(1-heterocycle) where R_(1-heterocycle) is as        defined above.

Also disclosed is a protected azide of formula (XII)

where R₂, R₃ and PROTECTING GROUP are as defined above and where R₁ is:

-   -   —CH₂-phenyl where -phenyl is substituted with two —F,    -   —(CH₂)_(n1)—R_(1-heteroaryl) where R_(1-hetroaryl) is as defined        above and    -   —(CH₂)_(n1)—R_(1-heterocycle) where R_(1-heterocycle) is as        defined above.

Further disclosed is a protected amine of formula (XIII)

where R₂, R₃ and PROTECTING GROUP are as defined above and where R₁ is:

-   -   —CH₂-phenyl where -phenyl is substituted with two —F,    -   —(CH₂)_(n1)—R_(1-heteroaryl) where R_(1-heteroaryl) is as        defined above and    -   —(CH₂)_(n1)—R_(1-heteroycle) where R_(1-heterocycle) is as        defined above.

Additionally disclosed is an unprotected azide of formula (XIV)

where R₁, R₂, R₃ and PROTECTING GROUP are as defined above for thesubstituted amine (X).

Further disclosed is an azide of formula (XV)

where R₁, R₂, R₃ and R_(N) are as defined above for the substitutedamine (X).

Also disclosed is a free amine of formula (XVI)

where R₂, R₃ and R_(N) are as defined above and where R₁ is:

-   -   (A) —CH₂-phenyl where -phenyl is substituted with two —F,    -   (B) —(CH₂)_(n1)—R_(1-heteroaryl) where R_(1-heteroaryl) is as        defined above and    -   (C) —(CH₂)_(n1)—R_(1-heterocycle) where R_(1-heterocycle) is as        defined above.

Disclosed is a method of treating a patient who has, or in preventing apatient from getting, a disease or condition selected from the groupconsisting of Alzheimer's disease, for helping prevent or delay theonset of Alzheimer's disease, for treating patients with mild cognitiveimpairment (MCI) and preventing or delaying the onset of Alzheimer'sdisease in those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, or diffuse Lewy body type of Alzheimer's disease and whois in need of such treatment which comprises administration of atherapeutically effective amount of a compound selected from the groupconsisting of a substituted amine of formula (X)

where R₁, R₂, R₃, R_(C), and R_(N) are as defined above for thesubstituted amine (X), and pharmaceutically acceptable salts thereof,anda substituted amine with R_(N) cyclized of formula (X′)

where R₁, R₂, R₃, R_(C), and Ring A, are as defined above for the amine(X′), and pharmaceutically acceptable salts thereof.

Also disclosed are methods for inhibiting beta-secretase activity, forinhibiting cleavage of amyloid precursor protein (APP), in a reactionmixture, at a site between Met596 and Asp597, numbered for the APP-695amino acid isotype; or at a corresponding site of an isotype or mutantthereof, for inhibiting production of amyloid beta peptide (A beta) in acell, for inhibiting the production of beta-amyloid plaque in an animal,and for treating or preventing a disease characterized by beta-amyloiddeposits in the brain which comprise administration of a therapeuticallyeffective amount of a substituted amine of formula (X)

where R₁, R₂, R₃, R_(C), and R_(N) are as defined above for thesubstituted amine (X), and pharmaceutically acceptable salts thereof.

Disclosed is a pharmaceutical composition which comprises a substitutedamine of formula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined above for thesubstituted amine (X), or a substituted amine with R_(N) cyclized offormula (X′)

where R₁ is as defined above for compound (X′) and where Ring A is asdefined above, and pharmaceutically acceptable salts thereof, and one ormore pharmaceutically acceptable inert carriers.

Disclosed is the use of a substituted amine of formula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined above for thesubstituted amine (X), or a substituted amine with R_(N) cyclized offormula (X′)

where R₁, R₂, R₃, R_(C), and Ring A, are as defined above for compound(X′), and pharmaceutically acceptable salts thereof for the manufactureof a medicament for use in treating a patient who has, or in preventinga patient from getting, a disease or condition selected from the groupconsisting of Alzheimer's disease, for helping prevent or delay theonset of Alzheimer's disease, for treating patients with mild cognitiveimpairment (MCI) and preventing or delaying the onset of Alzheimer'sdisease in those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, diffuse Lewy body type of Alzheimer's disease and who isin need of such treatment.

The present invention provides compounds, compositions, kits, andmethods for inhibiting beta-secretase-mediated cleavage of amyloidprecursor protein (APP). More particularly, the compounds, compositions,and methods of the invention are effective to inhibit the production ofA beta peptide and to treat or prevent any human or veterinary diseaseor condition associated with a pathological form of A beta peptide.

The compounds, compositions, and methods of the invention are useful fortreating humans who have Alzheimer's Disease (AD), for helping preventor delay the onset of AD, for treating patients with mild cognitiveimpairment (MCI), and preventing or delaying the onset of AD in thosepatients who would otherwise be expected to progress from MCI to AD, fortreating Down's syndrome, for treating Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch Type, for treating cerebral beta-amyloidangiopathy and preventing its potential consequences such as single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, fortreating dementia associated with Parkinson's disease, dementiaassociated with progressive supranuclear palsy, dementia associated withcortical basal degeneration, and diffuse Lewy body type AD.

The compounds of the invention possess beta-secretase inhibitoryactivity. The inhibitory activities of the compounds of the inventionare readily demonstrated, for example, using one or more of the assaysdescribed herein or known in the art.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is the substituted amines (X) that are useful intreating and preventing Alzheimer's disease. The anti-Alzheimer'ssubstituted amines (X) are made by methods well known to those skilledin the art from starting compounds known to those skilled in the art.The process chemistry is well known to those skilled in the art. Themost general process to prepare the substituted amines (X) of thepresent invention is set forth in CHART A. The chemistry is straightforward and in summary involves the steps of N-protecting an amino acid(I) starting material to produce the corresponding protected amino acid(II), reaction of the protected amino acid (II) with diazomethanefollowed by work-up to add a carbon atom to produce the correspondingprotected compound (III), reduction of the protected compound (III) tothe corresponding alcohol (IV), formation of the corresponding epoxide(V), opening of the epoxide (V) with a C-terminal amine, R_(C)—NH₂ (VI)to produce the corresponding protected alcohol (VII) which then has thenitrogen protecting group removed to produce the corresponding amine(VIII), which is then reacted with an amide forming agent of the formula(R_(N-1)—X_(N))₂O or R_(N-1)—X_(N)—X₂ or R_(N-1)—X_(N)—OH (IX) toproduce the anti-Alzheimer substituted amine (X). One skilled in the artwill appreciate that these are all well known reactions in organicchemistry. A chemist skilled in the art, knowing the chemical structureof the biologically active substituted amine end product (X) of theinvention would be able to prepare them by known methods from knownstarting materials without any additional information. The explanationbelow therefore is not necessary but is deemed helpful to those skilledin the art who desire to make the compounds of the present invention.

The backbone of the compounds of the present invention is ahydroxyethylamine moiety, —NH—CH(R)—CH(OH)—. It can be readily preparedby methods disclosed in the literature and known to those skilled in theart. For example, J. Med. Chem., 36, 288–291 (1992), TetrahedronLetters, 28, 5569–5572 (1987), J. Med. Chem., 38, 581–584 (1994) andTetrahedron Letters, 38, 619–620 (1997) all disclose processes toprepare hydroxyethylamine type compounds.

CHART A sets forth a general method used in the present invention toprepare the appropriately substituted amines (X). The anti-Alzheimersubstituted amines (X) of the present invention are prepared by startingwith the corresponding amino acid (I). The amino acids (I) are wellknown to those skilled in the art or can be readily prepared from knowncompounds by methods well known to those skilled in the art. Thesubstituted amines (X) of the present invention have at least twoenantiomeric centers which give four enantiomers. The first of theseenantiomeric centers derives from the amino acid starting material (I).It is preferred to commercially obtain or produce the desired enantiomer(S) rather than produce an enantiomerically impure mixture and then haveto separate out the desired enantiomer (S). It is preferred to start theprocess with enantiomerically pure (S)-amino acid (I) of the sameconfiguration as that of the substituted amine (X) product. For theamino acids (I), R₁ is:

-   (I) C₁–C₆ alkyl, optionally substituted with one, two or three    substituents selected from the group consisting of C₁–C₃ alkyl,    C₁–C₇ alkyl (optionally substituted with C₁–C₃ alkyl and C₁–C₃    alkoxy), —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy,    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,    —OC═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined    above,-   (II) —CH₂—S(O)₀₋₂—(C₁–C₆ alkyl),-   (III) —CH₂—CH₂—S(O)₀₋₂—(C₁–C₆ alkyl),-   (IV) C₂–C₆ alkenyl with one or two double bonds, optionally    substituted with one, two or three substituents selected from the    group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy,    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,-   (V) C₂–C₆ alkynyl with one or two triple bonds, optionally    substituted with one, two or three substituents selected from the    group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy,    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,-   (VI) —(CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero or one and where    R_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl,    dihydronaphthalyl, tetralinyl optionally substituted with one, two,    three, or four of the following substituents on the aryl ring:    -   (A) C₁–C₆ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁–C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b) where R_(1-a) and        R_(1-b) are as defined above, —C≡N, —CF₃, C₁–C₃ alkoxy,    -   (B) C₂–C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁–C₆ alkyl,    -   (C) C₂–C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃        alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or        C₁–C₆ alkyl,    -   (D) —F, Cl, —Br and —I,    -   (F) —C₁–C₆ alkoxy optionally substituted with one, two, or three        —F,    -   (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined        below,    -   (H) —OH,    -   (I) —C≡N,    -   (J) C₃–C₇ cycloalkyl, optionally substituted with one, two or        three substituents selected from the group consisting of —F,        —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,    -   (K) —CO—(C₁–C₄ alkyl),    -   (L) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as        defined above,    -   (M) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined        above,    -   (N) —SO₂—(C₁–C₄ alkyl),-   (VII) —(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ is as defined above    and where R_(1-heteroaryl) is selected from the group consisting of:    -   pyridinyl,    -   pyrimidinyl,    -   quinolinyl,    -   benzothienyl,    -   indolyl,    -   indolinyl,    -   pryidazinyl,    -   pyrazinyl,    -   isoindolyl,    -   isoquinolyl,    -   quinazolinyl,    -   quinoxalinyl,    -   phthalazinyl,    -   imidazolyl,    -   isoxazolyl,    -   pyrazolyl,    -   oxazolyl,    -   thiazolyl,    -   indolizinyl,    -   indazolyl,    -   benzothiazolyl,    -   benzimidazolyl,    -   benzofuranyl,    -   furanyl,    -   thienyl,    -   pyrrolyl,    -   oxadiazolyl,    -   thiadiazolyl,    -   triazolyl,    -   tetrazolyl,    -   oxazolopyridinyl,    -   imidazopyridinyl,    -   isothiazolyl,    -   naphthyridinyl,    -   cinnolinyl,    -   carbazolyl,    -   beta-carbolinyl,    -   isochromanyl,    -   chromanyl,    -   tetrahydroisoquinolinyl,    -   isoindolinyl,    -   isobenzotetrahydrofuranyl,    -   isobenzotetrahydrothienyl,    -   isobenzothienyl,    -   benzoxazolyl,    -   pyridopyridinyl,    -   benzotetrahydrofuranyl,    -   benzotetrahydrothienyl,    -   purinyl,    -   benzodioxolyl,    -   triazinyl,    -   phenoxazinyl,    -   phenothiazinyl,    -   pteridinyl,    -   benzothiazolyl,    -   imidazopyridinyl,    -   imidazothiazolyl,    -   dihydrobenzisoxazinyl,    -   benzisoxazinyl,    -   benzoxazinyl,    -   dihydrobenzisothiazinyl,    -   benzopyranyl,    -   benzothiopyranyl,    -   coumarinyl,    -   isocoumarinyl,    -   chromonyl,    -   chromanonyl,    -   pyridinyl-N-oxide    -   tetrahydroquinolinyl    -   dihydroquinolinyl    -   dihydroquinolinonyl    -   dihydroisoquinolinonyl    -   dihydrocoumarinyl    -   dihydroisocoumarinyl    -   isoindolinonyl    -   benzodioxanyl    -   benzoxazolinonyl    -   pyrrolyl N-oxide,    -   pyrimidinyl N-oxide,    -   pyridazinyl N-oxide,    -   pyrazinyl N-oxide,    -   quinolinyl N-oxide,    -   indolyl N-oxide,    -   indolinyl N-oxide,    -   isoquinolyl N-oxide,    -   quinazolinyl N-oxide,    -   quinoxalinyl N-oxide,    -   phthalazinyl N-oxide,    -   imidazolyl N-oxide,    -   isoxazolyl N-oxide,    -   oxazolyl N-oxide,    -   thiazolyl N-oxide,    -   indolizinyl N-oxide,    -   indazolyl N-oxide,    -   benzothiazolyl N-oxide,    -   benzimidazolyl N-oxide,    -   pyrrolyl N-oxide,    -   oxadiazolyl N-oxide,    -   thiadiazolyl N-oxide,    -   triazolyl N-oxide,    -   tetrazolyl N-oxide,    -   benzothiopyranyl S-oxide,    -   benzothiopyranyl S,S-dioxide,    -    where the R_(1-heteroaryl) group is bonded to —(CH₂)_(n1)— by        any ring atom of the parent R_(N-heteroaryl) group substituted        by hydrogen such that the new bond to the R_(1-heteroaryl) group        replaces the hydrogen atom and its bond, where heteroaryl is        optionally substituted with one, two, three, or four of:        -   (1) C₁–C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃,            C₁–C₃ alkoxy,        -   (2) C₂–C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁–C₆ alkyl,        -   (3) C₂–C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁–C₆ alkyl,        -   (4) —F, Cl, —Br and —I,        -   (6) —C₁–C₆ alkoxy optionally substituted with one, two, or            three of —F,        -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined below,        -   (8) —OH,        -   (9) —C≡N,        -   (10) C₃–C₇ cycloalkyl, optionally substituted with one, two            or three substituents selected from the group consisting of            —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy,            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆            alkyl,        -   (11) —CO—(C₁–C₄ alkyl),        -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (14) —SO₂—(C₁–C₄ alkyl), with the proviso that when n₁ is            zero R_(1-heteroaryl) is not bonded to the carbon chain by            nitrogen,-   (VIII) —(CH₂)_(n-1)—(R_(1-heterocycle)) where n₁ is as defined above    and R_(1-heterocycle) is selected from the group consisting of:    -   morpholinyl,    -   thiomorpholinyl,    -   thiomorpholinyl S-oxide,    -   thiomorpholinyl S,S-dioxide,    -   piperazinyl,    -   homopiperazinyl,    -   pyrrolidinyl,    -   pyrrolinyl,    -   tetrahydropyranyl,    -   piperidinyl,    -   tetrahydrofuranyl,    -   tetrahydrothienyl,    -   homopiperidinyl,    -   homomorpholinyl,    -   homothiomorpholinyl,    -   homothiomorpholinyl S,S-dioxide, and    -   oxazolidinonyl,    -   dihydropyrazolyl    -   dihydropyrrolyl    -   dihydropyrazinyl    -   dihydropyridinyl    -   dihydropyrimidinyl    -   dihydrofuryl    -   dihydropyranyl    -   tetrahydrothienyl S-oxide    -   tetrahydrothienyl S,S-dioxide    -   homothiomorpholinyl S-oxide    -    where the R_(1-heterocycle) group is bonded by any atom of the        parent R_(1-heterocycle) group substituted by hydrogen such that        the new bond to the R_(1-heterocycle) group replaces the        hydrogen atom and its bond, where heterocycle is optionally        substituted with one, two, three, or four of:        -   (1) C₁–C₆ alkyl optionally substituted with one, two or            three substituents selected from the group consisting of            C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —NR_(1-a)R_(1-b)            where R_(1-a) and R_(1-b) are as defined above, —C≡N, —CF₃,            C₁–C₃ alkoxy,        -   (2) C₂–C₆ alkenyl with one or two double bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁–C₆ alkyl,        -   (3) C₂–C₆ alkynyl with one or two triple bonds, optionally            substituted with one, two or three substituents selected            from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,            C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are            —H or C₁–C₆ alkyl,        -   (4) —F, Cl, —Br and —I,        -   (5) C₁–C₆ alkoxy,        -   (6) —C₁–C₆ alkoxy optionally substituted with one, two, or            three —F,        -   (7) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as            defined below,        -   (8) —OH,        -   (9) —C≡N,        -   (10) C₃–C₇ cycloalkyl, optionally substituted with one, two            or three substituents selected from the group consisting of            —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy,            —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆            alkyl,        -   (11) —CO—(C₁–C₄ alkyl),        -   (12) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (13) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (14) —SO₂—(C₁–C₄ alkyl),        -   (15) ═O, with the proviso that when n₁ is zero            R_(1-heterocycle) is not bonded to the carbon chain by            nitrogen. It is preferred that R₁ be —(CH₂)₀₋₁—(R_(1-aryl))            or —(CH₂)_(n1)—(R_(1-heteroaryl)). It is more preferred that            R₁ is —(CH₂)—(R_(1-aryl)) or —(CH₂)—(R_(1-heteroaryl)). It            is further preferred that R₁ is —(CH₂)—(R_(1-aryl)) where            R_(1-aryl) is phenyl. It is even more preferred that R₁ is            —(CH₂)—(R_(1-aryl)) where R_(1-aryl) is phenyl substituted            with two —F. It is additionally preferred that the —F            substitution is 3,5-difluorobenzyl.

When R₁ is R_(1-heteroaryl) or R_(1-heterocycle) the bond from theR_(1-heteroaryl) or R_(1-heterocycle) group to the —(CH₂)_(n1)— groupcan be from any ring atom which has an available valence provided thatsuch bond does not result in formation of a charged species or unstablevalence. This means that the R_(1-heteroaryl) or R_(1-heterocycle) groupis bonded to —(CH₂)_(n1)— by any ring atom of the parentR_(1-heteroaryl), or R_(1-heterocycle) group which was substituted byhydrogen such that the new bond to the R_(1-heteroaryl) orR_(1-heterocycle) group replaces the hydrogen atom and its bond.

The first step of the process is to protect the free amino group of the(S)-amino acid (I) with an amino protecting group to produce the(S)-protected amino acid (II) by methods well known to those skilled inthe art. Amino protecting groups are well known to those skilled in theart. See for example, “Protecting Groups in Organic Synthesis”, JohnWiley and sons, New York, N.Y., 1981, Chapter 7; “Protecting Groups inOrganic Chemistry”, Plenum Press, New York, N.Y., 1973, Chapter 2. Thefunction of the amino protecting group is to protect the free aminofunctionality (—NH₂) during subsequent reactions on the (S)-amino acid(I) which would not proceed well, either because the amino group wouldreact and be functionalized in a way that is inconsistent with its needto be free for subsequent reactions, or the free amino group wouldinterfere in the reaction. When the amino protecting group is no longerneeded, it is removed by methods well known to those skilled in the art.By definition the amino protecting group must be readily removable as isknown to those skilled in the art by methods well known to those skilledin the art. Suitable amino PROTECTING GROUP is selected from the groupconsisting of t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl,acetyl, trichloroacetyl, dichloroacetyl, chloroacetyl, trifluoroacetyl,difluoroacetyl, fluoroacetyl, 4-phenylbenzyloxycarbonyl,2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycabonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl,fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobornyloxycarbonyl and 1-piperidyloxycarbonyl, 9-fluorenylmethylcarbonate, —CH—CH═CH₂ and phenyl-C(═N—)—H. It is preferred that theprotecting group be t-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ),it is more preferred that the protecting group be t-butoxycarbonyl. Oneskilled in the art will understand the preferred methods of introducinga t-butoxycarbonyl or benzyloxycarbonyl protecting group and mayadditionally consult T. W. Green and P. G. M. Wuts in “Protective Groupsin Organic Chemistry,” John Wiley and Sons, 1991 for guidance.

The (S)-protected amino acid (II) is transformed to the corresponding(S)-protected compound (III) by two different methods depending on thenature of R₂ and R₃. R₂ and R₃ are independently selected from the groupconsisting of:

-   (I) —H,-   (II) C₁–C₆ alkyl, optionally substituted with one, two or three    substituents selected from the group consisting of C₁–C₃ alkyl, —F,    —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b)    where R_(1-a) and R_(1-b) are as defined above,-   (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or R_(1-heteroaryl)    where R_(1-aryl) and R_(1-heteroaryl) are as defined above;-   (IV) C₂–C₆ alkenyl with one or two double bonds,-   (V) C₂–C₆ alkynyl with one or two triple bonds,-   (VI) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionally substituted with one,    two or three substituents selected from the group consisting of —F,    —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where    R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, and where R₂ and R₃ are    taken together with the carbon to which they are attached to form a    carbocycle of three, four, five, six, and seven carbon atoms,    optionally where one carbon atom is replaced by a heteroatom    selected from the group consisting of —O—, —S—, —SO₂—, —NR_(N-2)—,    where R_(N-2) is as defined below. It is preferred that R₂ and R₃    both be —H. If R₂ and R₃ are not the same, an additional    enantiomeric center is added to the molecule. If it is desired that    both R₂ and R₃ are —H, then the (S)-protected amino acid (II) is    reacted with diazomethane, as is well known to those skilled in the    art, followed by reaction with a compound of the formula H-X₁ to    produce the (S)-protected compound (III). X₁ includes —Cl, —Br, —I,    —O-tosylate, —O-mesylate, —O-nosylate; it is preferred that —X₁ be    —Br or —Cl. Suitable reaction conditions include running the    reaction in inert solvents, such as but not limited to ether,    tetrahydrofuran and the like. The reactions from the (S)-protected    amino acid (II) to the (S)-protected compound (III) are carried out    for a period of time between 10 minutes and 1 day and at    temperatures ranging from −78 degrees to 20–25 degrees C. It is    preferred to conduct the reactions for a period of time between 1–4    hours and at temperatures between −30 degrees to −10 degrees C. This    process adds one methylene group.

Alternatively, the (S)-protected compounds of formula (III) can beprepared by first converting the (S)-protected amino acid (II) to acorresponding methyl or ethyl ester, according to methods wellestablished in the art, followed by treatment with a reagent of formulaX₁—C(R₂)(R₃)—X₁ and a strong metal base. The base serves to affect ahalogen-metal exchange, where the —X₁ undergoing exchange is a halogenselected from chlorine, bromine or iodine. The nucleophilic addition tothe ester derivative gives directly the (S)-protected compound (III).Suitable bases include, but are not limited to the alkyllithiumsincluding, for example, sec-butyllithium, n-butyllithium, andt-butyllithium. The reactions are preferably conducted at lowtemperature, such as −78 degrees C. Suitable reaction conditions includerunning the reaction in inert solvents, such as but not limited to,ether, tetrahydrofuran and the like. Where R₂ and R₃ are both hydrogen,then examples of X₁—C(R₂)(R₃)—X₁ include dibromomethane, diiodomethane,chloroiodomethane, bromoiodomethane and bromochloromethane. One skilledin the art knows the preferred conditions required to conduct thisreaction. Furthermore, if R₂ and/or R₃ are not —H, then by the additionof —C(R₂)(R₃)—X₁ to esters of the (S)-protected amino acid (II) toproduce the (S)-protected compound (III), an additional chiral centerwill be incorporated into the product, provided that R₂ and R₃ are notthe same.

The (S)-protected compound (III) is then reduced by means well known tothose skilled in the art for reduction of a ketone to the correspondingsecondary alcohol affording the corresponding alcohol (IV). The meansand reaction conditions for reducing the (S)-protected compound (III) tothe corresponding alcohol (IV) include, for example, sodium borohydride,lithium borohydride, borane, diisobutylaluminum hydride, and lithiumaluminium hydride. Sodium borohydride is the preferred reducing agent.The reductions are carried out for a period of time between 1 hour and 3days at temperatures ranging from −78 degrees C. to elevated temperatureup to the reflux point of the solvent employed. It is preferred toconduct the reduction between −78 degrees C. and 0 degrees C. If boraneis used, it may be employed as a complex, for example, borane-methylsulfide complex, borane-piperidine complex, or borane-tetrahydrofurancomplex. The preferred combination of reducing agents and reactionconditions needed are known to those skilled in the art, see forexample, Larock, R. C. in Comprehensive Organic Transformations, VCHPublishers, 1989. The reduction of the (S)-protected compound (III) tothe corresponding alcohol (IV) produces the second chiral center (thirdchiral center if R₂ and R₃ are not the same). The reduction of the(S)-protected compound (III) produces a mixture of enantiomers at thesecond center, (S, R/S)-alcohol (IV). This enantiomeric mixture is thenseparated by means known to those skilled in the art such as selectivelow-temperature recrystallization or chromatographic separation, forexample by HPLC, employing commercially available chiral columns. Theenantiomer that is used in the remainder of the process of CHART A isthe (S,S)-alcohol (IV) since this enantiomer will give the desiredbiologically active anti-Alzheimer (S,R)-substituted amine (X).

The (S,S)-alcohol (IV) is transformed to the corresponding epoxide (V)by means known to those skilled in the art. The stereochemistry of the(S)-(IV) center is maintained in forming the epoxide (V). A preferredmeans is by reaction with base, for example, but not limited to,hydroxide ion generated from sodium hydroxide, potassium hydroxide,lithium hydroxide and the like. Reaction conditions include the use ofC₁–C₆ alcohol solvents; ethanol is preferred. A common co-solvent, suchas for example, ethyl acetate may also be employed. Reactions areconducted at temperatures ranging from −45 degrees C. up to the refluxtemperature of the alcohol employed; preferred temperature ranges arebetween −20 degrees C. and 20–25 degrees C.

The epoxide (V) is then reacted with the appropriately substitutedC-terminal amine, R_(C)—NH₂ (VI) by means known to those skilled in theart that opens the epoxide to produce the desired correspondingenantiomerically pure (S,R)-protected alcohol (VII). The substitutedC-terminal amines, R_(C)—NH₂ (VI) of this invention are commerciallyavailable or are known to those skilled in the art and can be readilyprepared from known compounds. R_(C) includes:

-   (I) —C₁–C₁₀ alkyl optionally substituted with one, two or three    substituents selected from the group consisting of C₁–C₃ alkyl, —F,    —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl,    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    —OC═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined    above, —S(═O)₀₋₂ R_(1-a) where R_(1-a) is as defined above,    —NR_(1-a)C═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as    defined above, —C═O NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as    defined above, and —S(═O)₂ NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)    are as defined above,-   (II) —(CH₂)₀₋₃—(C₃–C₈) cycloalkyl where cycloalkyl can be optionally    substituted with one, two or three substituents selected from the    group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,    —CF₃, C₁–C₆ alkoxy, —O-phenyl, —CO—OH, —CO—O—(C₁–C₄ alkyl),    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,-   (III) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) where R_(C-x) and R_(C-y) are    -    —H,    -    C₁–C₄ alkyl optionally substituted with one or two —OH,    -    C₁–C₄ alkoxy optionally substituted with one, two, or three of        —F,    -    —(CH₂)₀₋₄–C₃–C₇ cycloalkyl,    -    C₂–C₆ alkenyl containing one or two double bonds,    -    C₂–C₆ alkynyl containing one or two triple bonds,    -    phenyl-,        and where R_(C-x) and R_(C-y) are taken together with the carbon        to which they are attached to form a carbocycle of three, four,        five, six and seven carbon atoms, optionally where one carbon        atom is replaced by a heteroatom selected from the group        consisting of —O—, —S—, —SO₂—, —NR_(N-2)— and R_(C-aryl) is        defined as R_(N-aryl) is defined below;-   (IV) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl) where R_(C-heteroaryl)    is defined as R_(N-heteroaryl) is defined above and R_(C-x) and    R_(C-y) are as defined above,-   (V) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-aryl) where R_(C-aryl),    R_(C-x) and R_(C-y) are as defined above,-   (VI) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-heteroaryl) where    R_(C-aryl), R_(C-heteroaryl), R_(C-x) and R_(C-y) are as defined    above,-   (VII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-aryl) where    R_(C-heteroaryl), R_(C-aryl), R_(C-x) and R_(C-y) are as defined    above,-   (VIII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-heteroaryl) where    R_(C-heteroaryl), R_(C-x) and R_(C-y) are as defined above,-   (IX) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-heterocycle) where    R_(C-aryl), R_(C-x) and R_(C-y) are as defined above, and    R_(C-heterocycle) is defined as R_(C-heterocycle) is defined below,-   (X) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-heterocycle) where    R_(C-heteroaryl) R_(C-heterocycle), R_(C-x) and R_(C-y) are as    defined above,-   (XI) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-aryl) where    R_(C-heterocycle), R_(C-aryl), R_(C-x) and R_(C-y) are as defined    above,-   (XII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-heteroaryl) where    R_(C-heterocycle), R_(C-heteroaryl), R_(C-x) and R_(C-y) are as    defined above,-   (XIII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-heterocycle)    where R_(C-heterocycle), R_(C-x) and R_(C-y) are as defined above,-   (XIV) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle) where    R_(C-heterocycle) is defined as R_(1-heterocycle) is defined above,    and R_(C-x) and R_(C-y) are as defined above,-   (XV) —[C(R_(C-1))(R_(C-2))]₁₋₃—CO—N—(R_(C-3))₂ where R_(C-1) and    R_(C-2) are the same or different and are selected from the group    consisting of:    -   (A) —H,    -   (B) —C₁–C₆ alkyl, optionally substituted with one, two or three        substituents selected from the group consisting of C₁–C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (C) C₂–C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (D) C₂–C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (E) —(CH₂)₁₋₂—S(O)₀₋₂—(C₁–C₆ alkyl),    -   (F) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionally substituted with one,        two or three substituents selected from the group consisting of        C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆        alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)        are as defined above,    -   (G) —(C₁–C₄ alkyl)—R_(C′-aryl) where R_(C′-aryl) is as defined        for R_(i-aryl),    -   (H) —(C₁–C₄ alkyl)—R_(C-heteroaryl) where R_(C-heteroaryl) is as        defined above,    -   (I) —(C₁–C₄ alkyl)—R_(C-heterocycle) where R_(C-heterocycle) is        as defined above,    -   (J) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined        above,    -   (K) —R_(C-heterocycle) where R_(C-heterocycle) is as defined        above,    -   (M) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₀₋₄—R_(C′-aryl) where R_(C-4) is —O—,        —S— or —NR_(C-5)— where R_(C-5) is C₁–C₆ alkyl, and where        R_(C′-aryl) is defined above,    -   (N) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₀₋₄—R_(C-heteroaryl) where R_(C-4)        and R_(C-heteroaryl) are as defined above,    -   (O) —R_(C′-aryl) where R_(C′-aryl) is as defined above, and        where R_(C-3) is the same or different and is:    -   (A) —H,    -   (B) —C₁–C₆ alkyl optionally substituted with one, two or three        substituents selected from the group consisting of C₁–C₃ alkyl,        —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl,        —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,    -   (C) C₂–C₆ alkenyl with one or two double bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (D) C₂–C₆ alkynyl with one or two triple bonds, optionally        substituted with one, two or three substituents selected from        the group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,        —C≡N, —CF₃, C₁–C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where        R_(1-a) and R_(1-b) are as defined above,    -   (E) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionally substituted with one,        two or three substituents selected from the group consisting of        C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆        alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)        are as defined above,    -   (F)—R_(C′-aryl) where R_(C′-aryl) is as defined above,    -   (G) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined        above,    -   (H) —R_(C-heterocycle) where R_(C-heterocycle) is as defined        above,    -   (I) —(C₁–C₄ alkyl)—R_(C′-aryl) where R_(C′-aryl) is as defined        above,    -   (J) —(C₁–C₄ alkyl)—R_(C-heteroaryl) where R_(C-heteroaryl) is as        defined above,    -   (K) —(C₁–C₄ alkyl)—R_(C-heterocycle) where R_(C-heterocycle) is        as defined above,-   (XVI) —CH(R_(C-aryl))₂ where R_(C-aryl) are the same or different    and are as defined above,-   (XVII) —CH(R_(C-heteroaryl))₂ where R_(C-heteroaryl) are the same or    different and are as defined above,-   (XVIII) —CH(R_(C-aryl))(R_(C-heteroaryl)) where R_(C-aryl) and    R_(C-heteroaryl) are as defined above,-   (XIX) -cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to    R_(C-aryl) or R_(C-heteroaryl) or R_(C-heterocycle) where R_(C-aryl)    or R_(C-heteroaryl) or R_(C-heterocycle) are as defined above where    one carbon of cyclopentyl, cyclohexyl, or -cycloheptyl is optionally    replaced with NH, NR_(N-5), O, S(═O)₀₋₂, and where cyclopentyl,    cyclohexyl, or -cycloheptyl can be optionally substituted with one    or two —C₁–C₃ alkyl, —F, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, ═O,    —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above,-   (XX) C₂–C₁₀ alkenyl containing one or two double bonds optionally    substituted with one, two or three substituents selected from the    group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,    —CF₃, C₁–C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and    R_(1-b) are as defined above,-   (XXI) C₂–C₁₀ alkynyl containing one or two triple bonds optionally    substituted with one, two or three substituents selected from the    group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,    —CF₃, C₁–C₆ alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and    R_(1-b) are as defined above,-   (XXI) —(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁—R_(C-aryl) where R_(C-aryl) is as    defined above and R_(C-6) is —(CH₂)₀₋₆—OH,-   (XXII) —(CH₂)₀₋₁—(CHR_(C-6)—(CH₂)₀₋₁—R_(C-heteroaryl) where    R_(C-heteroaryl) and R_(C-6) is as defined above,-   (XXIII) —CH(—R_(C-aryl) or R_(C-heteroaryl))—CO—O(C₁–C₄ alkyl) where    R_(C-aryl) and R_(C-heteroaryl) are as defined above,-   (XXIV) —CH(—CH₂—OH)—CH(—OH)-phenyl-NO₂,-   (XXV) (C₁–C₆ alkyl)—O—(C₁–C₆ alkyl)—OH,-   (XXVII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂,-   (XXVIII) —H,-   (XXIX) —(CH₂)₀₋₆—C(═NR_(1-a))(NR_(1-a)R_(1-b)) where R_(1-a) and    R_(1-b) are as defined above.    It is preferred that R_(C) is:    -   —C₁–C₈ alkyl,    -   —(CH₂)₀₋₃—(C₃–C₇) cycloalkyl,    -   —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl),    -   —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl),    -   —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle),    -   -cyclopentyl or -cyclohexyl ring fused to R_(C-aryl) or        R_(C-heteroaryl) or R_(C-heterocycle).        It is more preferred that R_(C) is:    -   —(CH₂)₀₋₃—(C₃–C₇) cycloalkyl,    -   —(CR_(C-x)R_(C-y))₀₋₄R_(C-aryl),    -   —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl),    -   —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle),    -   -cyclopentyl or -cyclohexyl ring fused to a R_(C-aryl) or        R_(C-heteroaryl) or R_(C-heterocycle).        It is even more preferred that R_(C) is:    -   —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl),    -   -cyclopentyl or -cyclohexyl ring fused to a R_(C-aryl) or        R_(C-heteroaryl) or R_(C-heterocycle).        It is still more preferred that R_(C) is selected from the group        consisting of:    -   —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) where R_(C-aryl) is phenyl,    -   —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl),    -   -cyclopentyl or -cyclohexyl ring fused to a R_(C-aryl) or        R_(C-heteroaryl) or R_(C-heterocycle). Further, it is preferred        that when R_(C) is phenyl, it is substituted in the 3-position        or 3,5-positions.

Suitable reaction conditions for opening the epoxide (V) include runningthe reaction in a wide range of common and inert solvents. C₁–C₆ alcoholsolvents are preferred and isopropyl alcohol most preferred. Thereactions can be run at temperatures ranging from 20–25 degrees C. up tothe reflux temperature of the alcohol employed. The preferredtemperature range for conducting the reaction is between 50 degrees C.up to the reflux temperature of the alcohol employed. When thesubstituted C-terminal amine (VI) is a 1-amino-3,5-cis-dimethylcyclohexyldicarboxylate it is preferrably prepared as follows. Todimethyl-5-aminoisophthalate in acetic acid and methanol, is addedrhodium in alumina in a high-pressure bottle. The bottle is saturatedwith hydrogen at 55 psi and shaken for one week of time. The mixture isthen filtered through a layer of diatomaceous earth and rinsed withmethanol three times, the solvents are removed under reduced pressure(with heat) to give a concentrate. The concentrate is triturated withether and filtered again to give the desired C-terminal amine (VI). Whenthe substituted C-terminal amine (VI) is 1-amino-3,5-cis-dimethoxycyclohexane it is prepared by following the general procedure above andmaking non-critical variations but starting with 3,5-dimethoxyaniline.When the substituted C-terminal amine (VI) is an aminomethyl group wherethe substituent on the methyl group is an aryl group, for exampleNH₂—CH₂—R_(C-aryl), and NH₂—CH₂—R_(C-aryl) is not commercially availableit is preferrably prepared as follows. A suitable starting material isthe (appropriately substituted) aralkyl compound. The first step isbromination of the alkyl substitutent via methods known to those skilledin the art, see for example R. C. Larock in Comprehensive OrganicTransformations, VCH Publishers, 1989, p.313. Next the alkyl halide isreacted with azide to produce the aryl-(alkyl)-azide. Last the azide isreduced to the corresponding amine by hydrogen/catalyst to give theC-terminal amine (VI) of formula NH₂—CH₂—R_(C-aryl). The suitablyfunctionalized C-terminal amines (VI) may readily be prepared by oneskilled in the art via known methods in the literature, makingnon-significant modifications. Select literature references include 1)Calderwood, et al., Tet. Lett., 1997, 38, 1241, 2) Ciganek, J. Org.Chem., 1992, 57,4521, 3) Thurkauf, et al., J. Med. Chem., 1990, 33,1452, 4) Werner, et al., Org. Syn., Coil. Vol. 5, 273, 5) J. Med. Chem.,1999, 42, 4193, 6) Chem. Rev. 1995, 95, 2457, 7) J. Am. Chem. Soc.,1986, 3150, 8) Felman et al., J. Med. Chem., 1992, 35, 1183, 9) J. Am.Chem. Soc. 1970, 92, 3700, 10) J. Med. Chem.,1997, 40, 2323.

CHART B discloses an alternative process for production of theenantiomerically pure (S,R)-protected alcohol (VII) from the(S)-protected compound (III). In the alternative process, the(S)-protected compound (III) is first reacted with the appropriatelysubstituted C-terminal amine R_(C)—NH₂ (VI) using the preferredconditions described above to produce the corresponding (S)-protectedketone (XI) which is then reduced using the preferred conditionsdescribed above to produce the corresponding (S,R)-protected alcohol(VII).

CHART C discloses another alternative process for production ofenantiomerically pure (S,R)-protected alcohol (VII) but this time fromthe epoxide (V). In the process of CHART C, the epoxide (V) is reactedwith azide to produce the corresponding enantiomerically pure(S,R)-protected azide (XII). Conditions to conduct the azide mediatedepoxide opening are known to those skilled in the art, see for example,J. March, Advanced Organic Chemistry, 3^(rd) Edition, John Wiley & SonsPublishers, 1985, p. 380. Next, the (S,R)-protected azide (XII) isreduced to the corresponding protected amine (XIII) by methods known tothose skilled in the art. Preferred reducing conditions to reduce the(S,R)-protected azide (XII) in the presence of a t-butoxycarbonylN-protecting group include catalytic hydrogenation, the conditions forwhich are known to those skilled in the art. Alternative reducingconditions which may be used to avoid N-deprotection with protectinggroups other than t-butoxycarbonyl are known to those skilled in theart, see for example, R. C. Larock in Comprehensive OrganicTransformations, VCH Publishers, 1989, p. 409.

The (S,R)-protected alcohol (VII) is deprotected to the corresponding(S,R)-amine (VIII) by means known to those skilled in the art forremoval of amine protecting group. Suitable means for removal of theamine protecting group depends on the nature of the protecting group.Those skilled in the art, knowing the nature of a specific protectinggroup, know which reagent is preferable for its removal. For example, itis preferred to remove the preferred protecting group, BOC, bydissolving the (S,R)-protected alcohol (VII) in a trifluoroaceticacid/dichloromethane mixture. When complete, the solvents are removedunder reduced pressure to give the corresponding (S,R)-amine (as thecorresponding salt, i.e. trifluoroacetic acid salt) which is usedwithout further purification. However, if desired, the (S,R)-amine canbe purified further by means well known to those skilled in the art,such as for example, recrystallization. Further, if the non-salt form isdesired that also can be obtained by means known to those skilled in theart, such as for example, preparing the free base amine via treatment ofthe salt with mild basic conditions. Additional BOC deprotectionconditions and deprotection conditions for other protecting groups canbe found in T. W. Green and P. G. M. Wuts in “Protective Groups inOrganic Chemistry,” John Wiley and Sons, 1991, p. 309. Typicalchemically suitable salts include trifluoroacetate, and the anion ofmineral acids such as chloride, sulfate, phosphate; preferred istrifluoroacetate and chloride.

The (S,R)-amine (VIII) is then reacted with an appropriately substitutedamide forming agent (IX) such as anhydride, acyl halide, or acid of theformula (R_(N-1)—X_(N))₂O or R_(N-1)—X_(N)—X₂ or R_(N-1)—X_(N)—OH (IX)by nitrogen-acylation means known to those skilled in the art to producethe corresponding (S,R)-substituted amine (X). Nitrogen acylationconditions for reaction of the (S,R)-amine (VIII) with an amide formingagent (IX) to produce the corresponding (S,R)-substituted amine (X) areknown to those skilled in the art and can be found in R. C. Larock inComprehensive Organic Transformations, VCH Publishers, 1989, p. 981,979, and 972. R_(N) includes:

-   (I) R_(N-1)—X_(N)— where X_(N) is selected from the group consisting    of:    -   (A) —CO—,    -   (B) —SO₂—,    -   (C) —(CR′R″)₁₋₆ where R′ and R″ are the same or different and        are —H and C₁–C₄ alkyl,    -   (D) —CO—(CR′R″)₁₋₆—X_(N-1) where X_(N-1) is selected from the        group consisting of —O—, —S— and —NR′— and where R′ and R″ are        as defined above,    -   (E) a single bond;-    where R_(N-1) is selected from the group consisting of:    -   (A) R_(N-aryl) where R_(N) aryl is phenyl, 1-naphthyl,        2-naphthyl, tetralinyl, indanyl, dihydronaphthyl or        6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, optionally        substituted with one, two or three of the following substituents        which can be the same or different and are:        -   (1) C₁–C₆ alkyl, optionally substituted with one, two or            three substituents selected from the group consisting of            C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃            alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (2) —OH,        -   (3) —NO₂,        -   (4) —F, —Cl, —Br, —I,        -   (5) —CO—OH,        -   (6) —C≡N,        -   (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3)            are the same or different and are selected from the group            consisting of:            -   (a) —H,            -   (b) —C₁–C₆ alkyl optionally substituted with one                substitutent selected from the group consisting of:                -   (i) —OH,                -   (ii) —NH₂,            -   (c) —C₁–C₆ alkyl optionally substituted with one, two or                three —F, —Cl, —Br, —I,            -   (d) —C₃–C₇ cycloalkyl,            -   (e) —(C₁–C₂ alkyl)—(C₃–C₇ cycloalkyl),            -   (f) —(C₁–C₆ alkyl)—O—(C₁–C₃ alkyl),            -   (g) —C₂–C₆ alkenyl with one or two double bonds,            -   (h) —C₂–C₆ alkynyl with one or two triple bonds,            -   (i) —C₁–C₆ alkyl chain with one double bond and one                triple bond,            -   (j) —R_(1-aryl) where R_(1-aryl) is as defined above,            -   (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as                defined above,        -   (8) —(CH₂)₀₋₄—CO—(C₁–C₁₂ alkyl),        -   (9) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkenyl with one, two or three            double bonds),        -   (10) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkynyl with one, two or three            triple bonds),        -   (11) —(CH₂)₀₋₄—CO—(C₃–C₇ cycloalkyl),        -   (12) —(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as defined            above,        -   (13) —CH₂)₀₋₄—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is            as defined above,        -   (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) where R_(1-heterocycle)            is as defined above,        -   (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from the            group consisting of morpholinyl, thiomorpholinyl,            piperazinyl, piperidinyl, homomorpholinyl,            homothiomorpholinyl, homothiomorpholinyl S-oxide,            homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl            where each group is optionally substituted with one, two,            three, or four of C₁–C₆ alkyl,        -   (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from            the group consisting of:            -   (a) C₁–C₆ alkyl,            -   (b) —(CH₂)₀₋₂—(R₁aryl) where R_(1-aryl) is as defined                above,            -   (c) C₂–C₆ alkenyl containing one or two double bonds,            -   (d) C₂–C₆ alkynyl containing one or two triple bonds,            -   (e) C₃–C₇ cycloalkyl,            -   (f) —(CH₂)₀₋₂—(R_(1-heteroaryl)) where R_(1-heteroaryl)                is as defined above,        -   (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3)            are as defined above,        -   (18) —(CH₂)₀₋₄—SO—(C₁–C₈ alkyl),        -   (19) —(CH₂)₀₋₄—SO₂—(C₁–C₁₂ alkyl),        -   (20) —(CH₂)₀₋₄—SO₂—(C₃–C₇ cycloalkyl),        -   (21) —(CH₂)₀₋₄N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can            be the same or different and is as defined above,        -   (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, where R_(N-5)            can be the same or different and is as defined above,        -   (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be the            same or different and is as defined above,        -   (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) where R_(N-5) and            R_(N-2) can be the same or different and are as defined            above,        -   (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can            be the same or different and are as defined above,        -   (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above,        -   (27) —(CH₂)₀₋₄—O—CO—(C₁–C₆ alkyl),        -   (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1) is            —H or C₁–C₄ alkyl,        -   (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (31) —(CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) is as defined            above,        -   (33) —(CH₂)₀₋₄—S—(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (34) —(CH₂)₀₋₄—O—(C₁–C₆ alkyl optionally substituted with            one, two, three, four or five of —F),        -   (35) C₃–C₇ cycloalkyl,        -   (36) C₂–C₆ alkenyl with one or two double bonds optionally            substituted with C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,            —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (37) C₂–C₆ alkynyl with one or two triple bonds optionally            substituted with C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,            —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5)            and R_(N-2) can be the same of different and are as            described above,        -   (39) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl,    -   (B) —R_(N-heteroaryl) where R_(N-heteroaryl) is selected from        the group consisting of:        -   pyridinyl,        -   pyrimidinyl,        -   quinolinyl,        -   benzothienyl,        -   indolyl,        -   indolinyl,        -   pryidazinyl,        -   pyrazinyl,        -   isoindolyl,        -   isoquinolyl,        -   quinazolinyl,        -   quinoxalinyl,        -   phthalazinyl,        -   imidazolyl,        -   isoxazolyl,        -   pyrazolyl,        -   oxazolyl,        -   thiazolyl,        -   indolizinyl,        -   indazolyl,        -   benzothiazolyl,        -   benzimidazolyl,        -   benzofuranyl,        -   furanyl,        -   thienyl,        -   pyrrolyl,        -   oxadiazolyl,        -   thiadiazolyl,        -   triazolyl,        -   tetrazolyl,        -   oxazolopyridinyl,        -   imidazopyridinyl,        -   isothiazolyl,        -   naphthyridinyl,        -   cinnolinyl,        -   carbazolyl,        -   beta-carbolinyl,        -   isochromanyl,        -   chromanyl,        -   tetrahydroisoquinolinyl,        -   isoindolinyl,        -   isobenzotetrahydrofuranyl,        -   isobenzotetrahydrothienyl,        -   isobenzothienyl,        -   benzoxazolyl,        -   pyridopyridinyl,        -   benzotetrahydrofuranyl,        -   benzotetrahydrothienyl,        -   purinyl,        -   benzodioxolyl,        -   triazinyl,        -   phenoxazinyl,        -   phenothiazinyl,        -   pteridinyl,        -   benzothiazolyl,        -   imidazopyridinyl,        -   imidazothiazolyl,        -   dihydrobenzisoxazinyl,        -   benzisoxazinyl,        -   benzoxazinyl,        -   dihydrobenzisothiazinyl,        -   benzopyranyl,        -   benzothiopyranyl,        -   coumarinyl,        -   isocoumarinyl,        -   chromonyl,        -   chromanonyl,        -   pyridinyl-N-oxide,        -   tetrahydroquinolinyl        -   dihydroquinolinyl        -   dihydroquinolinonyl        -   dihydroisoquinolinonyl        -   dihydrocoumarinyl        -   dihydroisocoumarinyl        -   isoindolinonyl        -   benzodioxanyl        -   benzoxazolinonyl        -   pyrrolyl N-oxide,        -   pyrimidinyl N-oxide,        -   pyridazinyl N-oxide,        -   pyrazinyl N-oxide,        -   quinolinyl N-oxide,        -   indolyl N-oxide,        -   indolinyl N-oxide,        -   isoquinolyl N-oxide,        -   quinazolinyl N-oxide,        -   quinoxalinyl N-oxide,        -   phthalazinyl N-oxide,        -   imidazolyl N-oxide,        -   isoxazolyl N-oxide,        -   oxazolyl N-oxide,        -   thiazolyl N-oxide,        -   indolizinyl N-oxide,        -   indazolyl N-oxide,        -   benzothiazolyl N-oxide,        -   benzimidazolyl N-oxide,        -   pyrrolyl N-oxide,        -   oxadiazolyl N-oxide,        -   thiadiazolyl N-oxide,        -   triazolyl N-oxide,        -   tetrazolyl N-oxide,        -   benzothiopyranyl S-oxide,        -   benzothiopyranyl S,S-dioxide,    -    where the R_(N-heteroaryl) group is bonded by any atom of the        parent R_(N-heteroaryl) group substituted by hydrogen such that        the new bond to the R_(N-heteroaryl) group replaces the hydrogen        atom and its bond, where heteroaryl is optionally substituted        with one, two three, or four of:        -   (1) C₁–C₆ alkyl, optionally substituted with one, two or            three substituents selected from the group consisting of            C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃            alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as            defined above,        -   (2) —OH,        -   (3) —NO₂,        -   (4) —F, —Cl, —Br, —I,        -   (5) —CO—OH,        -   (6) —C═N,        -   (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3)            are the same or different and are selected from the group            consisting of:            -   (a) —H,            -   (b) —C₁–C₆ alkyl optionally substituted with one                substitutent selected from the group consisting of:                -   (i) —OH,                -   (ii) —NH₂,            -   (c) —C₁–C₆ alkyl optionally substituted with one to                three —F, —Cl, —Br, —I,            -   (d) —C₃–C₇ cycloalkyl,            -   (e) —(C₁–C₂ alkyl)—(C₃–C₇ cycloalkyl),            -   (f) —(C₁–C₆ alkyl)—O—(C₁–C₃ alkyl),            -   (g) —C₂–C₆ alkenyl with one or two double bonds,            -   (h) —C₂–C₆ alkynyl with one or two triple bonds,            -   (i) —C₁–C₆ alkyl chain with one double bond and one                triple bond,            -   (j) —R_(1-aryl) where R_(1-aryl) is as defined above,            -   (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as                defined above,        -   (8) —(CH₂)₀₋₄—CO—(C₁–C₁₂ alkyl),        -   (9) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkenyl with one, two or three            double bonds),        -   (10) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkynyl with one, two or three            triple bonds),        -   (11) —(CH₂)₀₋₄—CO—(C₃–C₇ cycloalkyl),        -   (12) —(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as defined            above,        -   (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is            as defined above,        -   (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) where R_(1-heterocycle)            is as defined above,        -   (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from the            group consisting of morpholinyl, thiomorpholinyl,            piperazinyl, piperidinyl, homomorpholinyl,            homothiomorpholinyl, homothiomorpholinyl S-oxide,            homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl            where each group is optionally substituted with one, two,            three, or four of C₁–C₆ alkyl,        -   (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selected from            the group consisting of:            -   (a) C₁–C₆ alkyl,            -   (b) —(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as                defined above,            -   (c) C₂–C₆ alkenyl containing one or two double bonds,            -   (d) C₂–C₆ alkynyl containing one or two triple bonds,            -   (e) C₃–C₇ cycloalkyl,            -   (f) —(CH₂)₀₋₂—(R_(1-heteroaryl)) where R_(1-heteroaryl)                is as defined above,        -   (17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3)            are as defined above,        -   (18) —(CH₂)₀₋₄—SO—(C₁–C₈ alkyl),        -   (19) —(CH₂)₀₋₄—SO₂—(C₁–C₁₂ alkyl),        -   (20) —(CH₂)₀₋₄—SO₂—(C₃–C₇ cycloalkyl),        -   (21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5)            can be the same or different and is as defined above,        -   (22) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—N(R_(N-5))₂, where R_(N-5)            can be the same or different and is as defined above,        -   (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) can be the            same or different and is as defined above,        -   (24) —(CH₂)₀₋₄—N(—H or R_(N-5))—CO—R_(N-2) where R_(N-5) and            R_(N-2) can be the same or different and are as defined            above,        -   (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can            be the same or different and are as defined above,        -   (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above,        -   (27) —(CH₂)₀₋₄—O—CO—(C₁–C₆ alkyl),        -   (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂ where R_(N-aryl-1) is            —H or C₁–C₄ alkyl,        -   (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (31) —(CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) is as defined            above,        -   (33) —(CH₂)₀₋₄—S—(R_(N-5))₂ where R_(N-5) is as defined            above,        -   (34) —(CH₂)₀₋₄—O—(C₁–C₆ alkyl optionally substituted with            one, two, three, four, or five of —F),        -   (35) C₃–C₇ cycloalkyl,        -   (36) C₂–C₆ alkenyl with one or two double bonds optionally            substituted with C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,            —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (37) C₂–C₆ alkynyl with one or two triple bonds optionally            substituted with C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH,            —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) and            R_(1-b) are as defined above,        -   (38) —(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5)            and R_(N-2) can be the same or different and are as            described above,        -   (39) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl,    -   (C) R_(N-aryl)—W—R_(N-aryl),    -   (D) R_(N-aryl)—W—R_(N-heteroaryl),    -   (E) R_(N-aryl)—W—R_(N-1-heterocycle), where R_(N-heterocycle) is        defined as R_(1-heterocycle) is defined above,    -   (F) R_(N-heteroaryl)—W—R_(N-aryl),    -   (G) R_(N-heteroaryl)—W—R_(N-heteroaryl),    -   (H) R_(N-heteroaryl)—W—R_(N-1-heterocycle), where        R_(N-1-heterocycle) is defined as R_(1-heterocycle) is defined        above,    -   (I) R_(N-heterocycle)—W—R_(N-aryl),    -   (J) R_(N-heterocycle)—W—R_(N-heteroaryl),    -   (K) R_(N-heterocycle)—W—R_(N-1-heterocycle),    -    where W is        -   (1) —(CH₂)₀₋₄—,        -   (2) —O—,        -   (3) —S(O)₀₋₂—,        -   (4) —N(R_(N-5))— where R_(N-5) is as defined above, or        -   (5) —CO—;-   (II) —CO—(C₁–C₁₀ alkyl) where alkyl is optionally substituted with    one two, or three substitutents selected from the group consisting    of:    -   (A) —OH,    -   (B) —C₁–C₆ alkoxy,    -   (C) —C₁–C₆ thioalkoxy,    -   (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁–C₆ alkyl or -phenyl,    -   (E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (F) —CO—R_(N-4) where R_(N-4) is as defined above,    -   (G) —SO₂—(C₁–C₈ alkyl),    -   (H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (I) —NH—CO—(C₁–C₆ alkyl),    -   (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or        different and are as defined above,    -   (L) —R_(N-4) where R_(N-4) is as defined above,    -   (M) —O—CO—(C₁–C₆ alkyl),    -   (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8)s are the same or        different and are as defined above,    -   (O) —O—(C₁–C₅ alkyl)—COOH,    -   (P) —O—(C₁–C₆ alkyl optionally substituted with one, two, or        three of: —F, —Cl, —Br, —I),    -   (Q) —NH—SO₂—(C₁–C₆ alkyl),    -   (R) —F, —Cl,-   (III) —CO—(C₁–C₆ alkyl)—O—(C₁–C₆ alkyl) where alkyl is optionally    substituted with one, two, or three substitutents selected from the    group consisting of:    -   (A) —OH,    -   (B) —C₁–C₆ alkoxy,    -   (C) —C₁–C₆ thioalkoxy,    -   (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁–C₆ alkyl or -phenyl,    -   (E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (F) —CO—RN₄ where R_(N-4) is as defined above,    -   (G) —SO₂—(C₁–C₈ alkyl),    -   (H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (I) —NH—CO—(C₁–C₆ alkyl),    -   (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or        different and are as defined above,    -   (L) —R_(N-4) where R_(N-4) is as defined above,    -   (M) —O—CO—(C₁–C₆ alkyl),    -   (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8)s are the same or        different and are as defined above,    -   (O) —O—(C₁–C₅ alkyl)—COOH,    -   (P) —O—(C₁–C₆ alkyl optionally substituted with one, two, or        three of: —F, —Cl, —Br, —I),    -   (Q) —NH—SO₂—(C₁–C₆ alkyl),    -   (R) —F, —Cl,-   (IV) —CO—(C₁–C₆ alkyl)—S—(C₁–C₆ alkyl) where alkyl is optionally    substituted with one, two, or three substitutents selected from the    group consisting of:    -   (A) —OH,    -   (B) —C₁–C₆ alkoxy,    -   (C) —C₁–C₆ thioalkoxy,    -   (D) —CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (E) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (F) —CO—R_(N-4) where R_(N-4) is as defined above,    -   (G) —SO₂—(C₁–C₈ alkyl),    -   (H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same        or different and are as defined above,    -   (I) —NH—CO—(C₁–C₆ alkyl),    -   (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or        different and are as defined above,    -   (L) —R_(N-4) where R_(N-4) is as defined above,    -   (M) —O—CO—(C₁–C₆ alkyl),    -   (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8)s are the same or        different and are as defined above,    -   (O) —O—(C₁–C₅ alkyl)—COOH,    -   (P) —O—(C₁–C₆ alkyl optionally substituted with one, two, or        three of: —F, —Cl, —Br, —I),    -   (Q) —NH—SO₂—(C₁–C₆ alkyl),    -   (R) —F, —Cl,-   (V)    —CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl))    where R_(N-aryl) and R_(N-heteroaryl) are as defined above, where    R_(N-10) is selected from the group consisting of:    -   (A) —H,    -   (B) C₁–C₆ alkyl,    -   (C) C₃–C₇ cycloalkyl,    -   (D) C₂–C₆ alkenyl with one double bond,    -   (E) C₂–C₆ alkynyl with one triple bond,    -   (F) R_(1-aryl) where R_(1-aryl) is as defined above,    -   (G) R_(N-heteroaryl) where R_(N-heteroaryl) is as defined above,-   (VI) —CO—(C₃–C₈ cycloalkyl) where alkyl is optionally substituted    with one or two substitutents selected from the group consisting of:    -   (A) —(CH₂)₀₋₄—OH,    -   (B) —(CH₂)₀₋₄–C₁–C₆ alkoxy,    -   (C) —(CH₂)₀₋₄–C₁–C₆ thioalkoxy,    -   (D) —(CH₂)₀₋₄—CO—O—R_(N-8) where R_(N-8) is —H, C₁–C₆ alkyl or        -phenyl,    -   (E) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are        the same or different and are as defined above,    -   (F) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is as defined above,    -   (G) —(CH₂)₀₋₄—SO₂—(C₁–C₈ alkyl),    -   (H) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are        the same or different and are as defined above,    -   (I) —(CH₂)₀₋₄—NH—CO—(C₁–C₆ alkyl),    -   (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,    -   (K) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the        same or different and are as defined above,    -   (L) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above,    -   (M) —O—CO—(C₁–C₆ alkyl),    -   (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8)s are the same or        different and are as defined above;    -   (O) —O—(C₁–C₅ alkyl)—COOH,    -   (P) —O—(C₁–C₆ alkyl optionally substituted with one, two, or        three of: —F, —Cl, —Br, —I),    -   (Q) —NH—SO₂—(C₁–C₆ alkyl),    -   (R) —F, —Cl.        It is preferred that R_(N) is selected from the group consisting        of:

R_(N-1)—X_(N)— where X_(N) is —CO—, where R_(N-1) is R_(N-aryl) orR_(N-heteroaryl) where R_(N-aryl) is phenyl where the substitution onphenyl is 1,3-, and where R_(N-aryl) or R_(N-heteroaryl) are substitutedwith one —CO—NR_(N-2)R_(N-3),

R_(N-1)—X_(N)— where X_(N) is —CO—, where R_(N-1) is R_(N) aryl orR_(N-heteroaryl) where R_(N-aryl) is phenyl substituted with one C₁alkyl where the substitution on the phenyl is 1,3,5-, and whereR_(N-aryl) or R_(N-heteroaryl) are substituted with one—CO—NR_(N-2)R_(N-3),

R_(N-1)—X_(N)— where X_(N) is —CO—, where R_(N-1) is R_(N-heteroaryl)where R_(N-heteroaryl) is substituted with one —CO—NR_(N-2)R_(N-3) It isfurther preferred that R_(N-2) and R_(N-3) are the same and are C₃alkyl. It is further preferred that:

R_(N-1)—X_(N)— where X_(N) is —CO—, where R_(N-1) is R_(N-aryl) whereR_(N-aryl) is phenyl substituted with one —CO—NR_(N-2)R_(N-3) where thesubstitution on phenyl is 1,3-,

R_(N-1)—X_(N)— where X_(N) is —CO—, where R_(N-1) is R_(N-aryl) whereR_(N-aryl) is phenyl substituted with one C₁ alkyl and with one—CO—NR_(N-2)R_(N-3) where the substitution on the phenyl is 1,3,5-. Itis preferred that X_(N) is (A) —CO— and (B) —SO₂—; it is more preferredthat X_(N) be —CO—. X₂ includes —Cl, —Br; it is preferred that X₂ is—Cl.

The nitrogen-acylation of primary amines to produce secondary amides isone of the oldest known reactions. The amide forming agents,(R_(N-1)—X_(N))₂O or R_(N-1)—X_(N)—X₂ or R_(N-1)—X_(N)—OH (IX) are knownto those skilled in the art and are commercially available or can bereadily prepared from known starting materials by methods known in theliterature. It is preferred to use an isophthalic acid acylating agent(IX) of the formula R_(N-2)R_(N-3)N—CO-phenyl-CO— or a methylisophthalicacid acylating agent (IX) of the formulaR_(N-2)R_(N-3)N—CO—(CH₃—)phenyl-CO— where the substitution is5-methyl-1,3-isophthalic acid. The more preferred5-methyl-1,3-isophthalic acid is3-[(N,N-dipropylamino)carbonyl]-5-methylbenzoic acid (IX). Thesecompounds are preferably prepared as follows. An ester, preferably themonomethyl ester of isophthalic acid or methyl 5-methyl-1,3-isophthalateis dissolved in a THF/DMF mixture. 1,1′-Carbonyldiimidazole is added at20–25 degrees C. Next the desired amine (H-NR_(N-2)R_(N-3)) is added.After 3–24 hr of stirring at 20 degrees C. to the reflux temperature ofthe solvent, the reaction mixture is partitioned between saturatedaqueous ammonium chloride and a water immiscible organic solvent such asethyl acetate. The aqueous layer is separated and extracted twice morewith the organic solvent (ethyl acetate). The organic extracts arecombined and then washed with saturated aqueous solutions of bicarbonateand saline and dried over anhydrous sodium sulfate or magnesium sulfate.Filtration of the drying agent and removal of solvents by reducedpressure gives the methyl ester of the desiredR_(N-2)R_(N-3)N—CO-phenyl-CO—O—CH₃ or a methylisophthalic acid acylatingagent (IX) R_(N-2)R_(N-3)N—CO—(CH₃-)phenyl-CO—O—CH₃. Purification of the(methyl) ester can be achieved via chromatography on silica gel elutingwith ethyl acetate in hexanes. The isophthalate ester ormethylisophthalate ester of the mono-alkyl or di-alkyl amide is thentreated with an aqueous solution of base such as lithium hydroxide in aminimum amount of THF/methanol/water and stirred 3–24 hours at 20degrees C. to the reflux temperature of the solvent. The solvents arethen removed under reduced pressure and subsequently partitioned betweenwater and a water immiscible solvent such as ethyl acetate, for example.If emulsions prohibit separation of the two phases, a small amount ofsaline is added to aid in separation. The aqueous phase is separated andextracted once more with a water immiscible solvent such as ethylacetate, for example. The aqueous phase is then acidified withconcentrated acid, preferably hydrochloric until pH ≦3. The mixtureobtained is then extracted three times with a water immiscible solventsuch as ethyl acetate, for example. These combined organic extracts aredried over anhydrous sodium or magnesium sulfate. The drying agent isremoved by filtration and the organic solvent is removed under reducedpressure to give product. The mono- or di-alkyl amideisophthalate/methylisophthalate is used as such in the next reactionwith the (S,R)-amine (VIII) to produce the (S,R)-substituted amine (X).

When it is desired to produce a primary amide, R_(N-2) and R_(N-3) areboth —H, the following procedure is preferred. An ester, preferably themethyl ester of isophthalate or methyl 5-methyl-1,3-isophthalate isdissolved in a THF/DMF mixture. CDI is added at 20–25 degrees C. Afterfive to thirty minutes, ammonia gas is bubbled into the mixture througha syringe needle for 1 hr. The mixture is cooled to 0 degrees C. for theduration of the hour. The reaction is left stirring under a balloon ofammonia overnight at 20–25 degrees C., after which time the reactionmixture is partitioned between saturated aqueous ammonium chloride and awater immiscible solvent such as ethyl acetate, for example. The phasesare separated and the aqueous phase is extracted twice more with ethylacetate. The organic extracts are washed with saturated aqueoussolutions of bicarbonate and saline and dried over anhydrous sodium ormagnesium sulfate. Filtration of the drying agent and removal ofsolvents under reduced pressure gives the ester of the desiredisophthalic acid or the isophthalic acid acylating agent (IX).Purification of the (methyl) ester can be achieved via chromatography onsilica gel eluting with isopropanol/chloroform. The isophthalate esteror methylisophthalate ester of the primary amide is then treated with anaqueous solution of base such as lithium hydroxide in a minimum amountof THF/methanol/water and stirred overnight at 20–25 degrees C. afterwhich time the solvents are removed under reduced pressure andsubsequently partitioned between water and a water immiscible solventsuch as ethyl acetate, for example. If emulsions prohibit separation ofthe two phases, a small amount of saline is added to aid in separation.The aqueous phase is separated and extracted once more with a waterimmiscible solvent such as ethyl acetate, for example. The aqueous phaseis then acidified with concentrated acid, preferably hydrochloric untilpH ≦3. The mixture obtained is then extracted three times with ethylacetate. These combined organic extracts are dried over anhydrous sodiumor magnesium sulfate. The drying agent is removed by filtration and theorganic solvent removed under reduced pressure to give product. Theamide isophthalic acid is used as such in the next reaction with (VIII)to produce (X).

When it is desired that the amine be cyclized to be a group such asmorpholinyl, piperazinyl, piperidinyl and pyrrolidinyl, etc thefollowing procedure is preferably followed. An ester, preferably themethyl ester of isophthalic acid or methyl 5-methyl-1,3-isophthalate isdissolved in dry methylene chloride and three drops of DMF are added.The mixture is cooled to 0 degrees C. and then oxalyl chloride is added.The mixture is stirred at 0 degrees C. for 30 minutes to two hours afterwhich the solvents are removed under reduced pressure. The acid chlorideis left under vacuum overnight. The crude acid chloride is dissolved indry methylene and cooled to 0 degrees C. before the addition of thecyclic amine and a tertiary amine base such as N-methyl piperidine, forexample. The reaction mixture is stirred at 0 degrees C for I to 6 hrbefore the solvents are removed under reduced pressure. The residue isdiluted with water and a water immiscible solvent such as ethyl acetate,for example, and the phases are separated. The aqueous phase isextracted twice more with a water immiscible solvent such as ethylacetate, for example, and the combined organic extracts are washed withsaturated aqueous bicarbonate and dried over anhydrous sodium ormagnesium sulfate. Filtration of the drying agent and removal ofsolvents under reduced pressure gives the product cyclic amide. Thecyclic amide is then treated with an aqueous base such as lithiumhydroxide in a minimum amount of THF/methanol/water and stirredovernight at 20–25 degrees C., after which time the solvents are removedunder reduced pressure and the residue is subsequently partitionedbetween water and a water immiscible solvent such as ethyl acetate, forexample. The aqueous phase is extracted once more with ethyl acetate.Removal of water from the aqueous phase under reduced pressure gives thedesired cyclic amide product (IX).

When it is desired that R_(N-1) is carbocycle, for example but notlimited to, cyclohexane, one may then start with a suitablyfunctionalized dimethyl isophthalate and via methods taught in theliterature (Meyers, A. I., Org. Syn., 1971, 51, 103) one may reduce thesix-membered ring with reducing agents such as rhodium (5%) on aluminain the presence of acetic acid and methanol under a hydrogen atmosphereto afford the corresponding dimethyl cyclohexane dicarboxylate.

CHART D sets forth an alternative process for production of the(S,R)-substituted amine (X) from the (S,R)-protected azide (XII), whichis produced from the corresponding epoxide (V) in CHART C. The aminoprotecting group is removed to produce the corresponding unprotectedazide (XIV) by methods previously described in CHART A for theconversion of (S,R)-protected alcohol (VII) to the corresponding(S,R)-amine (VIII). The (S,R)-unprotected azide (XIV) is then acylatedon nitrogen to produce the corresponding (S,R)-azide (XV). Next, theazide functionality is reduced as previously discussed for theconversion of the (S,R)-protected azide (XII) to the corresponding(S,R)-protected amine (XIII) to give the (S,R)-free amine (XVI). Last,the (S,R)-free amine (XVI) is transformed to the corresponding(S,R)-substituted amine (X) by nitrogen alkylation with a compound ofthe formula R_(C)—X₃ to give the corresponding (S,R)-substituted amine(X). X₃ is an appropriate leaving group, such as but not limited to,—Cl, —Br, —I, —O-mesylate, —O-tosylate, O-triflate, etc. X₃ may also bean aldehyde; the corresponding coupling with (XVI) via the well knownreductive amination procedure gives the (S,R)-substituted amine (X).

Carbocylic amide forming agents (IX) are also provided for by theinvention. For example, the carbocyclic amide forming agents of theformula

(IX) are readily prepared from known starting materials by methodsdisclosed in the literature and known to those skilled in the art, forexample, J. Med. Chem. 1998, 41, 1581, J Org. Chem. 2000, 65, 1305. Itis also understood that instead of the carboxylic acid, one may readilyemploy an acyl halide, where the halide is preferably choride, or asuitable group to produce a mixed anhydride; these methods are taught byCHART A. For additional guidance on the formation of carbocyles andpreferably cyclopropanes, one may consult M. P. Doyle; M. A. McKervery;T. Ye in Modern Catalytic Methods for Organic Synthesis with DiazoCompounds From Cyclopropanes to Ylides, Wiley-Interscience, 1998, pp.163–279.

CHARTs E, F, G, and H disclose various methods to produce the R_(N)portion of the substituted amine (X) where the phenyl ring of the R_(N)1,3-disubstituted moiety, —CO-phenyl-CO—, is further substituted in the5-position with various groups such as amides, nitrites, halides, andamines. These compounds are prepared by methods known to those skilledin the art. The process chemistry of each reaction is known to thoseskilled in the art. What is novel here is the order of each process stepand/or the specific reactants used. One skilled in the art knowing thedesired product would know at least one method to prepare the desiredproduct by using known starting materials. Hence, the followingdiscussion is not necessary but is set forth to further aid thoseinterested in preparing the compounds of the invention.

CHART E discloses alternate processes for the transformation of theaniline (XVII) or acid ester (XVIII) to the corresponding acid(IX–XXIII). One process begins with the commercially available aniline(XVII) where R_(N-a) is preferably —H, C₁–C₄ alkyl or benzyl. Theaniline (XVII) is treated with a diazotizing reagent such as sodium orpotassium nitrite in mineral acid, followed by a halogen source such ascopper (II) halide or alkali metal halide, or by an organic diazotizingreagent such as an alkyl nitrite in a strong acid such as acetic acid ortrifluoroacetic acid, followed by a halide source such as copper (II)halide or alkali metal halide to give the halo acid ester (XIX) whereR_(N-b) is —Cl, —Br or —I. Alternatively, the acid ester (XVIII) istreated with N-halosuccinimide and trifluoromethanesulfonic acid to givethe halo acid ester (XIX). The halo acid ester (XIX) is then convertedto the ester amide (XXI) using a primary or secondary amine of theformula H—NR_(Nalpha)R_(Nbeta) (AMINE) where R_(Nalpha) and R_(Nbeta)are the same or different or can be cyclized. These groups, R_(Nalpha)and R_(Nbeta), become part of the substituted amine (X) and are includedin the definition of R_(N). R_(N) includes R_(N-1)—X_(N)— where thelinker, —X_(N)—, includes —CO— and R_(N-1) includes R_(N-aryl).R_(N-aryl) is defined to include phenyl (-phenyl) optionally substitutedwith two amides:

—CO—NR_(N-2)R_(N-3) and

—CO—R_(N-4). R_(Nalpha) and R_(Nbeta) include both the non-cyclicamides, —CO—NR_(N-2)R_(N-3) and the cyclic amides-CO—R_(N-4) whereR_(N-2), R_(N-3) and R_(N-4) are as defined in the claims.Alternatively, the halo acid ester (XIX) is converted to the dihaloester (XX) by methods known to those skilled in the art. R_(N) includes—Cl and —F. The dihalo ester (XX) is treated with a primary or secondaryamine of the formula H-NR_(Nalpha)R_(Nbeta) (AMINE) to give the esteramide (XXI). The ester amide (XXI) is then reacted with an AMINE in acarbon monoxide atmosphere in the presence of a palladium catalyst usingmethods such as those reviewed by Heck, (Palladium Reagents in OrganicSynthesis, 1985 pp. 342–365). to give the diamide (XXII). Hydrolysis ofthe ester portion of the diamide (XXII) using methods well known tothose skilled in the art gives the diamide acid (XXIII).

In CHART F, an alterate route to intermediate diamide (XXII) is shownstarting from commercially available phenol (XXIV). The phenol (XXIV) istreated with a trifluoromethanesulfonating reagent such astrifluoromethanesulfonic anhydride to give triflate (XXV). The triflate(XXV) is reacted under the conditions of palladium catalysis in thepresence of carbon monoxide and an amine of the formulaH—NR_(Nalpha)R_(Nbeta) (AMINE) as for the conversion of the ester amide(XXI) to the corresponding diamide (XXII) in CHART E to give the diester(XXVI). The diester (XXVI) is hydrolyzed using methods known to thoseskilled in the art to give the monoacid (XXVII). The monoacid (XXVII) isthen converted to the diamide (XXII) using conditions such as for theconversion of the halo acid ester (XIX) to the ester amide (XXI) inCHART E.

CHART G discloses another route to prepare the ester amide (XXI). Thereaction starts with commercially available nitro compound (XXVIII)which is condensed with an (AMINE) using coupling methods known to thoseskilled in the art to give the nitro amide (XXX). The nitro amide (XXX)can also be prepared by first treating the nitro compound (XXVIII) withreagents such as thionyl chloride, or DMF and oxalyl chloride, or othermethods known to those skilled in the art to give the acid chloride(XXIX), which upon treatment with the (AMINE) gives the nitro amide(XXX). Reduction of the nitro amide (XXX) using methods known to thoseskilled in the art (see, for example, Smith and March, Advanced OrganicChemistry, 5^(th) ed.) gives amide aniline (XXXI). The amide aniline(XXXI) is then treated with diazotizing reagents such as sodium orpotassium nitrite in mineral acid, followed by a halogen source such ascopper (II) halide or alkali metal halide, or by an organic diazotizingreagent such as an alkyl nitrite in a strong acid such as acetic acid ortrifluoroacetic acid, followed by a halide source such as copper (II)halide or alkali metal halide to give the ester amide (XXI).

CHART H discloses a process to prepare the diamide acid (IX–XXIII) fromthe ester amide (XXI), where one of the amides is unsubstituted and is—CO—NH₂. This process starts from either the ester or the acid, forexample the ester amide (XXI) is treated with copper (I) cyanide (CuCN)in N-methylpyrrolidinone or DMF, preferably N-methylpyrrolidinone, togive the nitrite (XXXII). The nitrile (XXXII) is converted to theprimary amide (XXXIII) using urea-hydrogen peroxide complex (see Synth.Commun. (1993) 3149) or the methods of Synth. Commun. (1990) 1445,Synth. Commun. (1997) 3119, J Org. Chem. (1992) 2521, Tet. Lett. (1996)6555, Ind. J. Chem., Sect. B, (1999) 974, Tet. Lett. (1995) 3469, Tet.Lett. (1998) 3005, or others. When the ester amide (XXI) is in the formof an ester, an additional hydrolysis step using lithium hydroxide,sodium hydroxide, potassium hydroxide, barium hydroxide, or otherhydrolysis methods known to those skilled in the art is used to convertthe diamide ester (XXXIII) to the diamide acid (IX–XXIII).

CHART I discloses an alternate synthetic route from the protectedalcohol (VII) to the substituted amine (X) which uses a diprotectedintermediate (XXXIV) whereby the nitrogen atom attached to the R_(C)substitutent is protected. Using the process of CHART I, the monoprotected alcohol (VII) is reacted with a new protecting group to formthe orthogonally protected (XXXIV). This is a common strategy employedin traditional peptide chemistry by those skilled in the art, see M.Bodansky, Principles of Peptide Chemistry. When the mono protectedalcohol (VII) is protected with CBZ one skilled in the art could reactit with either (BOC)₂O in methylene chloride or similar organic solventor FMOC—Cl in methylene chloride or similar organic solvent to prepareorthogonally protected (XXXIV). Then the CBZ group is removed byhydrogenation in the presence of a catalytic amount of palladium oncarbon in an alcoholic solvent, such as methanol, or ethyl acetate, orwith catalytic palladium on carbon in alcoholic solvents in the presenceof ammonium formate as is known to those skilled in the art. This givesthe R_(C)—N protected (XXXV). Similarly, when the mono protected alcohol(VII) is protected as a BOC it can be reacted with CBZ-Cl underSchotten-Bauman conditions or CBZ-OSu in THF to prepare the reversed(XXXIV). Then the BOC group can be cleaved with hydrochloric acid (4 N)in methanol, ethanol or dioxane or with trifluoroacetic acid inmethylene chloride or by other methods such as those described in ThePeptides, Analysis, Synthesis, Biology, Vol. 3, Ed. E. Gross and J.Meienhofer (1981) to liberate the CBZ R_(C)—N protected (XXXV). Thisfunctional group manipulation gives various permutations in the sequence(VII) to (XXXIV) to (XXXV) as is apparent to one skilled in the art.When the appropriately R_(C)—N protected compound (XXXV) is reacted withthe amide forming agent (IX), in acid form, under standard peptidecoupling conditions, for example, EDC/HOBt in methylene chloride or DMFor a previously activated acid, (R_(N)—)₂O gives the correspondingR_(N)-substituted R_(C)—N protected (XXXVI). Simple de-protection of theR_(N)-substituted R_(C)—N protected (XXXVI) then gives the desiredsubstituted amine (X). Thus when the R_(N)-substituted R_(C)—N protected(XXXVI) is protected with BOC, treatment with hydrochloric acid (4N) indioxane or the other reagents discussed above gives the substitutedamine (X). When the R_(N)-substituted R_(C)—N protected (XXXVI) isprotected with CBZ, treatment with hydrogen from 10–50 psi in alcoholicsolvents, such as methanol with a catalytic amount of palladium oncarbon will give, after work-up, the desired substituted amine (X).Similarly when the R_(N-substituted) R_(C)—N protected (XXXVI) isprotected with FMOC, treatment with a secondary amine, preferably eitherpiperidine (10%) or diethylamine (10%) in an inert solvent such as, forexample, methylene chloride will give after work up the desiredsubstituted amine (X).

CHART J discloses a process to prepare compounds where the phenyl ringof the R_(N) substituent of —CO-phenyl-CO— is substituted with asulfonamide group in the 5-position. The process starts with the haloamide ester (XXI, CHART E) which is reacted with sodium nitrite, sulfurdioxide, copper chloride (II) and acetic acid by the method disclosed inJ. Med. Chem., 42, 3797 (1999) to prepare the sulfonyl chloride(XXXVII). The sulfonyl chloide (XXXVII) is then reacted with AMINE, asdefined above, by methods known to those skilled in the art to producethe corresponding sulfonamide (XXXVIII). Last the sulfonamide (XXXVIII)is transformed to the corresponding sulfonamide acid (XXMX) by methodsknown to those skilled in the art such as using lithium hydroxide,sodium hydroxide, potassium hydroxide, barium hydroxide, or otherhydrolysis methods known to those skilled in the art.

CHART K discloses how to prepare the R_(N) substituents where R_(N) isR_(N-1)—X_(N)—, where X_(N) is —CO— and R_(N-1) is R_(N-aryl) whereR_(N-aryl) is phenyl substituted with one alkyl group and one—CO—NR_(N-2)R_(N-3) or —CO—R_(N-4). See the discussion above for CHART Eregarding the amine, H—NR_(Nalpha)R_(Nbeta) (AMINE), used to form theamide R_(N) substituents. The process starts with the halo amide ester(XXI) which is then reacted with an alkyl boronic acid having thedesired alkyl group in the presence of a palladium catalyst such asPd(PPh₃)Cl₂ using the general method described in J. Med. Chem., 4288(2000). The alkyl boronic acids are commercially available or can beprepared by the process described in J. Am. Chem. Soc., 60, 105 (1938).It is preferred that R_(N-b) is bromo. This step produces the alkylester (XL) which is then hydrolyzed by means known to those skilled inthe art to produce the desired alkyl acid (XLI).

CHART L discloses a process to prepare the amide forming agent(IX–XLVII) where the R_(N) substituent is R_(N-1)—X_(N)—, where thelinker, —X_(N)— is —CO—, where R_(N-1) is R_(N-aryl) and whereR_(N-aryl) is phenyl (-phenyl) substituted with groups:

C₁–C₆ alkyl, optionally substituted with one, two or three substituentsselected from the group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, and —N(—H and C₁–C₃ alkyl)—CO—R_(N-5).This specific amide forming agent, (IX–XLVII) is prepared by startingwith the phenyl nitro compound (XLII) which is reduced to thecorresponding phenyl nitro hydroxy compound (XLIII) using borane-methylsulfide or borane in THF. The phenyl nitro hydroxy compound (XLIII) isreduced to the corresponding phenyl amino hydroxy compound (XLIV) usinghydrogen and palladium catalyst as is known to those skilled in the art.The phenyl amino hydroxy compound (XLIV) is reacted with an aldehyde inthe presence of a reducing agent such as sodium cyanoborohydride orsodium triacetoxyborohydride to give the phenyl substituted aminohydroxy compound (XLV). The phenyl substituted amino hydroxy compound(XLV) is acylated with an acid chloride or acid anhydride by methodsknown to those skilled in the art to give the phenyl disubstituted aminohydroxy compound (XLVI). The phenyl disubstituted amino hydroxy compound(XLVI) is hydrolyzed using an alkali hydroxide, followed byacidification, to give the amide forming agent (IX–XLVII). The amideforming agent (XLVII) is then coupled with amine (VIII) using methodsknown to those skilled in the art and methods previously discussed, suchas with diethyl cyanophosphonate, to give the substituted amine (X).Further treatment of the substituted amine (X) with diethylcyanophosphonate gives the substituted amine where the hydroxyalkylsubstitutent on the phenyl ring has a phosphate substitutent.

CHART M discloses a process to prepare amide forming agents (IX–L) wherethe R_(N) substituent is R_(N-1)—X_(N)—, where the linker, —X_(N)— is—CO—, where R_(N-1) is R_(N-aryl) and where R_(N-aryl) is phenyl(-phenyl) substituted with two groups. The first substituent at what isusually identified as position “5-” can be either:

-   -   —R_(N-aryl) or    -   —R_(N-heteroaryl). The second substituent at what is usually        identified as postion “3-” can be either:    -   —CO—NR_(N-2)R_(N-3) or    -   —CO—R_(N-4). R_(Nalpha) and R_(Nbeta) include both the        non-cyclic amides,—CO—NR_(N-2)R_(N-3) and the cyclic        amides-CO—R_(N-4) where R_(N-2), R_(N-3) and R_(N-4) are as        defined in the claims. The process starts with the        trisubstituted phenyl compound (XLVIII) where R_(N-d) is —Cl,        —Br, —I or —O-triflate. Treatment with an aryl or heteroaryl        boronic acid or heteroaryl or aryl boronic acid ester such as        (aryl or heteroaryl)-B(OH)₂ or (aryl or        heteroaryl)-B(OR^(a))(OR^(b)) (where R^(a) and R^(b) are lower        alkyl, ie. C₁–C₆, or taken together, R^(a) and R^(b) are lower        alkylene, ie. C₂–C₁₂) in the presence of a metal catalyst with        or without a base in an inert solvent yields (XLIX). Metal        catalysts in these transformations include, but are not limited        to, salts or phosphine complexes of Cu, Pd, or Ni (eg. Cu(OAc)₂,        PdCl₂(PPh₃)₂, NiCl₂(PPh₃)₂). Bases may include, but are not        limited to, alkaline earth metal carbonates, alkaline earth        metal bicarbonates, alkaline earth metal hydroxides, alkali        metal carbonates, alkali metal bicarbonates, alkali metal        hydroxides, alkali metal hydrides (preferably sodium hydride),        alkali metal alkoxides (preferably sodium methoxide or sodium        ethoxide), alkaline earth metal hydrides, alkali metal        dialkylamides (preferably lithium diisopropylamide), alkali        metal bis(trialkylsilyl)amides (preferably sodium        bis(trimethylsilyl)amide), trialkyl amines (preferably        diisopropylethylamine or triethylamine) or aromatic amines        (preferably pyridine). Inert solvents may include, but are not        limited to, acetonitrile, dialkyl ethers (preferably diethyl        ether), cyclic ethers (preferably tetrahydrofuran or        1,4-dioxane), N,N-dialkylacetamides (preferably        dimethylacetamide), N,N-dialkylformamides (preferably        dimethylformamide), dialkylsulfoxides (preferably        dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or        toluene) or haloalkanes (preferably methylene chloride).        Preferred reaction temperatures range from room temperature up        to the boiling point of the solvent employed. The reactions may        be run in conventional glassware or in one of many commercially        available parallel synthesizer units. Non-commercially available        boronic acids or boronic acid esters may be obtained from the        corresponding optionally substituted aryl halide as described in        Tetrahedron, 50, 979–988 (1994). Intermediate (XLIX) is then        hydrolyzed using alkali metal hydroxide, for example lithium,        sodium or potassium hydroxide, followed by acidification, to        give aryl or heteroaryl coupled acids (IX–L). Alternatively, as        described in Tetrahedron, 50, 979–988 (1994), one may convert        the R_(N-d) to the corresponding boronic acid or boronic acid        ester (OH)₂B— or (OR^(a))(OR^(b))B— and obtain the same products        set forth above by treating with a suitable aryl or heteroaryl        halide or triflate.

CHART N discloses a process to prepare amide forming agents (IX–LII)where the R_(N) substituent is R_(N1)—X_(N)— where the linker, —X_(N)—is —CO—, where R_(N-1) is R_(N-aryl) and where R_(N-aryl) is phenyl(-phenyl) substituted with two groups. The first substitutent at what isusually identified as postion “5-” is —C≡C—R. The second substituent atwhat is usually identified as postion “3-” can be either—CO—NR_(N-2)R_(N-3) or —CO—R_(N-4). The halo ester (XXI) is treated witha mixture of PdCl₂(Pphenyl₃)₂ and trimethylsilyl acetylene, usingmethods known to those skilled in the art, to give acetylene ester (LI).Acetylene ester (LI) is then hydrolyzed using alkali metal hydroxide,followed by acidification, to give acetylene acid (IX–LII).

CHARTs O and O′ disclose processes to prepare amide forming agents(IX–LX) and (IX–LXIII) with an extended methylene group where the R_(N)substituent is R_(N-1)—X_(N)— where the linker, —X_(N)— is —CO—, whereR_(N-1) is R_(N-aryl) and where R_(N-aryl) is phenyl (-phenyl)substituted with two groups. The substituent at what is usuallyidentified as postion “3-” can be either —CO—NR_(N-2)R_(N-3) or—CO—R_(N-4). In the process of CHART O, the substituent at the5-position is —CH₂CO—NH₂ and in the process of CHART O′, the substituentat the 5-position is —CH₂C—N. The starting diester acid (LIII) isreduced with borane in solvents such as THF to give the correspondingdiester alcohol (LIV). The diester alcohol (LIV) is converted to thecorresponding diester bromo compound (LV) using a brominating agent suchas PBr₃, CBr₄, or other halogenating agent such as are known to thoseskilled in the art. The bromine of the diester bromo compound (LV) isthen displaced with cyanide to give the corresponding nitrile (LVI). InCHART O′, the nitrile (LVI) is then hydrolyzed to the correspondingcyano ester (LXI). The cyano ester (LXI) is then coupled withH—NR_(Nα)R_(Nβ) (AMINE), as previously described using methods known tothose skilled in the art to give the corresponding cyano amide (LXII).The cyano amide (LXII) is then hydrolyzed to the corresponding cyanoacid (IX–LXIII) which is in turn coupled with amine (VIII) to give thesubstituted amine (X). When the substitutent on the extended methylgroup is —CO—NH₂, the process of CHART O is used. There the nitrile(LVI) is converted to the corresponding diester amine (LVII) by methodsknown to those skilled in the art. The next steps are the same as forCHART O′ where the diester amide (LVII) is hydrolyzed to thecorresponding ester amine (LVIII) which is then converted to thecorresponding diamide ester (LIX) which is hydrolyzed to thecorresponding diamide acid (IX–LX). The diamide acid (IX–XL) is thencoupled with the appropriate amine (VIII) to produce the desiredsubstituted amide (X).

CHART P discloses a process to prepare amide forming agents (IX–LXVII)with an extended hydroxymethylene group where the R_(N) substituent isR_(N-1)—X_(N)— where the linker, —X_(N)— is —CO—, where the R_(N-1) isR_(N-aryl), where R_(N-aryl) is phenyl (-phenyl) substituted with twogroups. The substituent at what is usually identified as position “3-”can be either —CO—NR_(N-2)R_(N-3) or —CO—R_(N-4). The process beginswith a halo amide (LXIV), preferably iodo, which is converted to thecorresponding aldehyde (LXV) and then to the corresponding alcohol(LXVI) by the method described in Synth. Commun. 28, 4270 (1998),optionally with variations known to those skilled in the art. Hydrolysisof the alcohol (LXVI) using alkali hydroxides, followed byacidification, gives the desired hydroxy acid (IX–LXVII). The hydroxyacid (IX–LXVII) is then coupled with the appropriate amine (VIII) togive the desired substituted amine (X).

CHART Q discloses a process to prepare amide forming agents (IX–LXXII)with an alkyl group or a halogen atom or an amino group at the5-position where the R_(N) substituent is R_(N-1)—X_(N)— where thelinker, —X_(N)— is —CO—, where the R_(N-1) is R_(N-aryl), whereR_(N-aryl) is phenyl (-phenyl) substituted with two groups. Thesubstituent at what is usually identified as position “3-” can be either—CO—NR_(N-2)R_(N-3) or —CO—R_(N-4). The process begins with anappropriately 5-substituted diacid (LXVIII) which is esterified bymethods known to those skilled in the art to give the correspondingdiester (LXIX). The diester (LXIX) is then hydrolyzed using alkalihydroxides, followed by acidification, to give the correspondingmonoacid (LXX). Alternatively, the monoacid (LXX) can be produceddirectly from the diacid (LXVIII) by known methods. The monoacid (LXX)is then coupled with H—NR_(Nalpha)R_(Nbeta) (AMINE) to give thecorresponding amide ester (LXXI). The amide ester (LXXI) is thenhydrolyzed using alkali hydroxides, followed by acidification, to givethe corresponding acid amide (IX–LXXII).

CHART R discloses a general process to prepare the amide forming agents(IX–LXXVII) which, for example, have an alkyl group at what is known asthe 5-position and a ketone at the 3-position. These acids (IX–LXXVII)are formed by starting with the acid (LXXIII) which is converted to thecorresponding acid halide (LXXIV) using methods known to those skilledin the art. The acid halide (LXXIV) is preferrably the acid chloride.The acid halide (LXXIV) in the presence of copper (I) bromide andtetrahydrofuran and at temperatures ranging from −78 degrees C. to 0degrees C. is treated with a Grignard reagent (aryl-Mg-X, or alkyl-Mg—X,where X is —Cl or —Br) to give the ketone esters (LXXVI and LXXVI′).Many Grignard reagents are available for purchase; others are preparedby methods known to those skilled in the art. An alternative method forpreparing the ketone esters (LXXVI, LXXVI′) is to prepare the Weinrebamide (LXXV), either from the acid (LXXIII) directly or by way of acidhalide (LXXIV) followed by treatment with N,O-dimethylhydroxylamine togive Weinreb amide (LXXV) and then treating the Weinreb amide (LXXV)with a Grignard reagent, by methods known to those skilled in the art.The ketone esters (LXXVI, LXXVI′) are then hydrolyzed using alkalihydroxides, followed by acidification, to give the ketone acids (LXXVII,LXXVII′).

CHART S discloses various methods to modify the R_(N) portion of thesubstituted amine (X) where the phenyl ring of the R_(N) moiety isfurther substituted in the 3-position with various groups such as aryland heteroaryl. These compounds are prepared by methods known to thoseskilled in the art. The process chemistry of each reaction is known tothose skilled in the art. What is novel here is the order of eachprocess step and/or the specific reactants used. One skilled in the artknowing the desired product would know at least one method to preparethe desired product by using known starting materials. Hence, thefollowing discussion is not necessary but is set forth to further aidthose interested in preparing the compounds of the invention.

CHART S sets forth a general method used in the present invention toprepare the substituted amines (X) whereR_(N)═R_(N-aryl)—R_(N-aryl)—X_(N) or R_(N-heteroaryl)—R_(N-aryl)—X_(N).Treatment of the (S,R)-amine (VIII) with amide forming agents (IX)according to the methods set forth above where for CHART S, R_(N-1) isBr—R_(N-aryl) generates the corresponding (S,R)-substituted amine (X)where R_(N) is Br—N_(R-aryl)—X_(N). Further treatment with an arylboronic acid or aryl boronic acid ester such as (aryl orheteroaryl)—B(OH)₂ or (aryl or heteroaryl)—B(OR^(a))(OR^(b)) (whereR^(a) and R^(b) are lower alkyl, ie. C₁–C₆, or taken together, R^(a) andR^(b) are lower alkylene, ie. C₂–C₁₂) in the presence of a metalcatalyst with or without a base in an inert solvent yields the(S,R)-substituted amine (X) where R_(N) is N_(R-aryl)—N_(R-aryl)—X_(N)or R_(N-heteroaryl)—R_(N-aryl)—X_(N). Metal catalysts in thesetransformations include, but are not limited to, salts or phosphinecomplexes of Cu, Pd, or Ni (eg. Cu(OAc)₂, PdCl₂(PPh₃)₂, NiCl₂(PPh₃)₂).Bases may include, but are not limited to, alkaline earth metalcarbonates, alkaline earth metal bicarbonates, alkaline earth metalhydroxides, alkali metal carbonates, alkali metal bicarbonates, alkalimetal hydroxides, alkali metal hydrides (preferably sodium hydride),alkali metal alkoxides (preferably sodium methoxide or sodium ethoxide),alkaline earth metal hydrides, alkali metal dialkylamides (preferablylithium diisopropylamide), alkali metal bis(trialkylsilyl)amides(preferably sodium bis(trimethylsilyl)amide), trialkyl amines(preferably diisopropylethylamine or triethylamine) or aromatic amines(preferably pyridine). Inert solvents may include, but are not limitedto, acetonitrile, dialkyl ethers (preferably diethyl ether), cyclicethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylacetamides (preferably dimethylacetamide),N,N-dialkylformamides (preferably dimethylformamide), dialkylsulfoxides(preferably dimethylsulfoxide), aromatic hydrocarbons (preferablybenzene or toluene) or haloaalkanes (preferably methylene chloride).Preferred reaction temperatures range from room temperature up to theboiling point of the solvent employed. The reactions may be run inconventional glassware or in one of many commercially available parallelsynthesizer units. Non-commercially available boronic acids or boronicacid esters may be obtained from the corresponding optionallysubstituted aryl halide as described in Tetrahedron, 50, 979–988 (1994).

Where the above chemistry is incompatible with other functionalitypresent in the (S,R)-substituted amine (X) where R_(N) isBr—N_(R-aryl)—X_(N), then one skilled in the art will readily understandthat an alternative sequence of coupling steps is required. For example,treatment of an appropriately substituted amide forming agent (IX)R_(N-1)—X_(N)—OH where R_(N-1) is Br—R_(N-aryl) with a boronic acid orboronic acid ester under the conditions described above will afford theappropriately substituted amide forming agent (IX) where R_(N-1) isN_(R-aryl)—N_(R-aryl) or R_(N-heteroaryl)—R_(N-aryl). When the amideforming agent (IX) where R_(N-1) is N_(R-aryl)—N_(R-aryl) orR_(N-heteroaryl)—R_(N-aryl) is treated with the (S,R)-amine (VIII), onethen obtains the same substituted amines (X) set forth in CHART S.

The above examples for CHART S are not meant to limit the scope of thechemistry. In addition to bromine, a suitable group may include iodineor triflate. Alternatively, as described in Tetrahedron, 50, 979–988(1994), one may convert the Br—R_(N-aryl) to the corresponding boronicacid or boronic acid ester (OH)₂B—R_(N-aryl) or(OR^(a))(OR^(b))B—R_(N-aryl) and obtain the same products set forthabove by treating with a suitable aryl or heteroaryl halide or triflate.Additionally, each —R_(N-aryl) and —R_(N-heteroaryl) are interchangeableat each occurrence in the chemistry described above.

CHART T discloses a process to prepare amide forming agents (IX–LXXIX)where the R_(N) substituent is R_(N-1)—X_(N)—, where the linker, —X_(N)—is —CO—, where RN—, is R_(N-aryl) and where R_(N-aryl) is phenylsubstituted with —CO—NR_(Nalpha)R_(Nbeta) (AMINE) and with an amide ofthe formulas:—(CH₂)₀₋₄—N(—H and R_(N-5))—CO—R_(N-2)—(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2).

The process begins with the amide aniline (XXXI) which is reacted withthe corresponding acid halide or sulfonyl halide, or acid anhydride orsulfonyl anhydride to produce the corresponding amide ester (LXXVIII).Suitable solvents include TBF or dichloromethane at temperatures rangingfrom −78 degrees to 100 degrees C. The amide ester (LXXVIII) is thenhydrolyzed to the corresponding amide acid (IX–LXXIX) by methods knownto those skilled in the art. When the amide forming agent (IX–LXXIX) isreacted with the appropriate amine (VIII), the desired substituted amine(X) is obtained.

CHART U discloses a general method for preparing various C-terminalamines (VI) as represented by the preparation of C-terminal amine(LXXXIV). Methods to prepare amines of this type are well understoodusing methods known to those skilled in the art, or one may consult thereferences: 1) JACS, 1970, 92, 3700, and 2) U.S. Pat. No. 4,351,842.

CHART V further discloses general methods for preparing variousC-terminal amines (VI) as represented by the preparation of C-terminalamines (LXXXIX). Multiple examples of the heterocyclic carboxylic acidsor acid chlorides are commercially available. Optionally, the carboxylicacid (LXXXV) may be converted to the acid chloride (LXXXVI) withreagents such as, but not limited to, thionyl chloride. Displacementwith ammonia generates the common intermediate amides (LXXXVII) whichare readily reduced to amines (VI–LXXXIX) using a variety of methodsdetailed previously. Alternatively, other heteroaryls are commerciallyavailable as the methyl halide (LXXXVIII) which are treated with ammoniato yield the title C-terminal amines (VI–LXXXVIII).

CHART W discloses general methods for preparing thiazolyl containingC-terminal amines as represented by the preparation of C-terminal amines(LXXXXI). The synthesis of the thiazoles is outlined in CHART W; theseprocedures are amply taught in the literature and are modified from theprocedures outlined in: Mashraqui, S H; Keehn, P M. J. Am. Chem. Soc.1982, 104,44614465. The synthesis of substituted 5-aminomethylthiazoles(XCI) was achieved from 5-hydroxymethylthiazole (XC) by the proceduredescribed in: Alterman et al. J. Med. Chem. 1998, 41, 3782–3792. Allother thiazole analogs were transformed to the hydroxymethyl derivativeusing CHART W, and converted to the aminomethyl derivative by theAlterman procedure without notable changes.

CHART X discloses general methods for preparing isoxazolyl containingC-terminal amines as represented by the preparation of C-terminal amines(XCII). The synthesis of isoxazole derivatives was modified from theprocedure in: Felman, S W et al. J. Med. Chem. 1992, 35, 1183–1190 andis readily understood by those skilled in the art making non-notablechanges to achieve the title compounds. The substituted hydroxylamineprecursors were synthesized using the procedure taught by Bousquet, E W.Org. Synth. Coll. Vol II, 313–315. Commercially available propargylaminemay be protected using any number of methods known in the art (see:Greene, T W; Wuts, P G M. Protective Groups in Organic Synthesis, 3^(rd)Ed. New York: John Wiley, 1999. Chapter 7.), prefered is a BOCprotecting group. Substituted propargyl amines may be obtained by anumber of methods commonly known in the art.

CHART Y discloses a general route to prepare hydroxyethylamines whereone carbon atom of the peptide backbone, along with R₂ and R₃ form aring. It is understood that the present invention also allows for aheteroatom to be incorporated into the ring. In summary, the synthesisof compounds where R₂ and R₃ may form a ring proceeds from a suitablyprotected amino acid aldehyde and cycloalkyllithium species, both ofwhich are commercially available or where known procedures for makingsuch compounds are known in the art. The general procedure involved isalso precedent in the literature, for example, see Klumpp, et al., J.Am. Chem. Soc., 1979, 101, 7065, and it is intended that makingnon-critical variations, one may obtain the title compounds provided forby CHART Y. Treatment of a suitably protected amino acid aldehyde andcycloalkyllithium species affords alcohol (XCIII). These reactions arecarried out in an inert solvent such as, for example, tetrahydrofuran ordiethyl ether. Optimally the reactions are conducted at lowtemperatures, for example below 0 degrees C. Carbonylation via theKlumpp procedure yields the acid (XCIV) which when exposed to Curtius,or related procedures well known to those skilled in the art, generatesthe primary amine (XCV). The primary amines (XCV) may be cappedC-terminally via the conditions set forth in CHART C & D followed bynitrogen deprotection and capping N-terminally via the conditions setforth in CHART A.

The compounds of the invention may contain geometric or optical isomersas well as tautomers. Thus, the invention includes all tautomers andpure geometric isomers, such as the E and Z geometric isomers, as wellas mixtures thereof. Futhermore, the invention includes pure enantiomersand diasteriomers as well as mixtures thereof, including racemicmixtures. The individual geometric isomers, enantiomers, ordiasteriomers may be prepared or isolated by methods known in the art.

Compounds of the invention with the stereochemistry designated informula X may be included in mixtures, including racemic mixtures, withother enantiomers, diasteriomers, geometric isomers or tautomers.Compounds of the invention with the stereochemistry designated informula X are typically present in these mixtures in excess of 50percent. Preferably, compounds of the invention with the stereochemistrydesignated in formula X are present in these mixtures in excess of 80percent. Most preferably, compounds of the invention with thestereochemistry designated in formula X are present in these mixtures inexcess of 90 percent.

The (S,R)-substituted amines (X) and the substituted amine with R_(N)cyclized (X′) are amines and as such form salts when reacted with acids.Pharmaceutically acceptable salts are preferred over the corresponding(S,R)-substituted amines (X) and and the substituted amines with R_(N)cyclized (X′) since they produce compounds which are more water soluble,stable and/or more crystalline. Pharmaceutically acceptable salts areany salt which retains the activity of the parent compound and does notimpart any deleterious or undesirable effect on the subject to whom itis administered and in the context in which it is administered.Pharmaceutically acceptable salts include salts of both inorganic andorganic acids. The preferred pharmaceutically acceptable salts includesalts of the following acids acetic, aspartic, benzenesulfonic, benzoic,bicarbonic, bisulfuiric, bitartaric, butyric, calcium edetate, camsylic,carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl,esylic, formic, fumaric, gluceptic, gluconic, glutamic,glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic,hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic,lactobionic, maleic, malic, malonic, mandelic, methanesulfonic,methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic,p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogenphosphoric, dihydrogen phosphoric, phthalic, polygalactouronic,propionic, salicylic, stearic, succinic, succinic, sulfamic, sulfanilic,sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic. Forother acceptable salts, see Int. J. Pharm., 33, 201–217 (1986) andJ.Pharm.Sci., 66(1), 1, (1977).

The present invention provides compounds, compositions, kits, andmethods for inhibiting beta-secretase enzyme activity and A beta peptideproduction. Inhibition of beta-secretase enzyme activity halts orreduces the production of A beta from APP and reduces or eliminates theformation of beta-amyloid deposits in the brain.

Methods of the Invention

The compounds of the invention, and pharmaceutically acceptable saltsthereof, are useful for treating humans or animals suffering from acondition characterized by a pathological form of beta-amyloid peptide,such as beta-amyloid plaques, and for helping to prevent or delay theonset of such a condition. For example, the compounds are useful fortreating Alzheimer's disease, for helping prevent or delay the onset ofAlzheimer's disease, for treating patients with MCI (mild cognitiveimpairment) and preventing or delaying the onset of Alzheimer's diseasein those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobal hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, and diffuse Lewy body type Alzheimer's disease. Thecompounds and compositions of the invention are particularly useful fortreating or preventing Alzheimer's disease. When treating or preventingthese diseases, the compounds of the invention can either be usedindividually or in combination, as is best for the patient.

As used herein, the term “treating” means that the compounds of theinvention can be used in humans with at least a tentative diagnosis ofdisease. The compounds of the invention will delay or slow theprogression of the disease thereby giving the individual a more usefullife span.

The term “preventing” means that the compounds of the present inventionare useful when administered to a patient who has not been diagnosed aspossibly having the disease at the time of administration, but who wouldnormally be expected to develop the disease or be at increased risk forthe disease. The compounds of the invention will slow the development ofdisease symptoms, delay the onset of the disease, or prevent theindividual from developing the disease at all. Preventing also includesadministration of the compounds of the invention to those individualsthought to be predisposed to the disease due to age, familial history,genetic or chromosomal abnormalities, and/or due to the presence of oneor more biological markers for the disease, such as a known geneticmutation of APP or APP cleavage products in brain tissues or fluids.

In treating or preventing the above diseases, the compounds of theinvention are administered in a therapeutically effective amount. Thetherapeutically effective amount will vary depending on the particularcompound used and the route of administration, as is known to thoseskilled in the art.

In treating a patient displaying any of the diagnosed above conditions aphysician may administer a compound of the invention immediately andcontinue administration indefinitely, as needed. In treating patientswho are not diagnosed as having Alzheimer's disease, but who arebelieved to be at substantial risk for Alzheimer's disease, thephysician should preferably start treatment when the patient firstexperiences early pre-Alzheimer's symptoms such as, memory or cognitiveproblems associated with aging. In addition, there are some patients whomay be determined to be at risk for developing Alzheimer's through thedetection of a genetic marker such as APOE4 or other biologicalindicators that are predictive for Alzheimer's disease. In thesesituations, even though the patient does not have symptoms of thedisease, administration of the compounds of the invention may be startedbefore symptoms appear, and treatment may be continued indefinitely toprevent or delay the outset of the disease.

Dosage Forms and Amounts

The compounds of the invention can be administered orally,parenternally, (IV, IM, depo-IM, SQ, and depo SQ), sublingually,intranasally (inhalation), intrathecally, topically, or rectally. Dosageforms known to those of skill in the art are suitable for delivery ofthe compounds of the invention.

Compositions are provided that contain therapeutically effective amountsof the compounds of the invention. The compounds are preferablyformulated into suitable pharmaceutical preparations such as tablets,capsules, or elixirs for oral administration or in sterile solutions orsuspensions for parenternal administration. Typically the compoundsdescribed above are formulated into pharmaceutical compositions usingtechniques and procedures well known in the art.

About 1 to 500 mg of a compound or mixture of compounds of the inventionor a physiologically acceptable salt or ester is compounded with aphysiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, flavor, etc., in a unit dosage form as calledfor by accepted pharmaceutical practice. The amount of active substancein those compositions or preparations is such that a suitable dosage inthe range indicated is obtained. The compositions are preferablyformulated in a unit dosage form, each dosage containing from about 2 toabout 100 mg, more preferably about 10 to about 30 mg of the activeingredient. The term “unit dosage from” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

To prepare compositions, one or more compounds of the invention aremixed with a suitable pharmaceutically acceptable carrier. Upon mixingor addition of the compound(s), the resulting mixture may be a solution,suspension, emulsion, or the like. Liposomal suspensions may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. The form of theresulting mixture depends upon a number of factors, including theintended mode of administration and the solubility of the compound inthe selected carrier or vehicle. The effective concentration issufficient for lessening or ameliorating at least one symptom of thedisease, disorder, or condition treated and may be empiricallydetermined.

Pharmaceutical carriers or vehicles suitable for administration of thecompounds provided herein include any such carriers known to thoseskilled in the art to be suitable for the particular mode ofadministration. In addition, the active materials can also be mixed withother active materials that do not impair the desired action, or withmaterials that supplement the desired action, or have another action.The compounds may be formulated as the sole pharmaceutically activeingredient in the composition or may be combined with other activeingredients.

Where the compounds exhibit insufficient solubility, methods forsolubilizing may be used. Such methods are known and include, but arenot limited to, using cosolvents such as dimethylsulfoxide (DMSO), usingsurfactants such as Tween(D, and dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as salts or prodrugs mayalso be used in formulating effective pharmaceutical compositions.

The concentration of the compound is effective for delivery of an amountupon administration that lessens or ameliorates at least one symptom ofthe disorder for which the compound is administered. Typically, thecompositions are formulated for single dosage administration.

The compounds of the invention may be prepared with carriers thatprotect them against rapid elimination from the body, such astime-release formulations or coatings. Such carriers include controlledrelease formulations, such as, but not limited to, microencapsulateddelivery systems. The active compound is included in thepharmaceutically acceptable carrier in an amount sufficient to exert atherapeutically useful effect in the absence of undesirable side effectson the patient treated. The therapeutically effective concentration maybe determined empirically by testing the compounds in known in vitro andin vivo model systems for the treated disorder.

The compounds and compositions of the invention can be enclosed inmultiple or single dose containers. The enclosed compounds andcompositions can be provided in kits, for example, including componentparts that can be assembled for use. For example, a compound inhibitorin lyophilized form and a suitable diluent may be provided as separatedcomponents for combination prior to use. A kit may include a compoundinhibitor and a second therapeutic agent for co-administration. Theinhibitor and second therapeutic agent may be provided as separatecomponent parts. A kit may include a plurality of containers, eachcontainer holding one or more unit dose of the compound of theinvention. The containers are preferably adapted for the desired mode ofadministration, including, but not limited to tablets, gel capsules,sustained-release capsules, and the like for oral administration; depotproducts, pre-filled syringes, ampules, vials, and the like forparenternal administration; and patches, medipads, creams, and the likefor topical administration.

The concentration of active compound in the drug composition will dependon absorption, inactivation, and excretion rates of the active compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

If oral administration is desired, the compound should be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

Oral compositions will generally include an inert diluent or an ediblecarrier and may be compressed into tablets or enclosed in gelatincapsules. For the purpose of oral therapeutic administration, the activecompound or compounds can be incorporated with excipients and used inthe form of tablets, capsules, or troches. Pharmaceutically compatiblebinding agents and adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches, and the like can contain any ofthe following ingredients or compounds of a similar nature: a bindersuch as, but not limited to, gum tragacanth, acacia, corn starch, orgelatin; an excipient such as microcrystalline cellulose, starch, orlactose; a disintegrating agent such as, but not limited to, alginicacid and corn starch; a lubricant such as, but not limited to, magnesiumstearate; a gildant, such as, but not limited to, colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; and aflavoring agent such as peppermint, methyl salicylate, or fruitflavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials, whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, chewing gum orthe like. A syrup may contain, in addition to the active compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings, and flavors.

The active materials can also be mixed with other active materials thatdo not impair the desired action, or with materials that supplement thedesired action.

Solutions or suspensions used for parenternal, intradermal,subcutaneous, or topical application can include any of the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oil, a naturally occurring vegetable oil such as sesameoil, coconut oil, peanut oil, cottonseed oil, and the like, or asynthetic fatty vehicle such as ethyl oleate, and the like, polyethyleneglycol, glycerine, propylene glycol, or other synthetic solvent;antimicrobial agents such as benzyl alcohol and methyl parabens;antioxidants such as ascorbic acid and sodium bisulfite; chelatingagents such as ethylenediaminetetraacetic acid (EDTA); buffers such asacetates, citrates, and phosphates; and agents for the adjustment oftonicity such as sodium chloride and dextrose. Parenternal preparationscan be enclosed in ampoules, disposable syringes, or multiple dose vialsmade of glass, plastic, or other suitable material. Buffers,preservatives, antioxidants, and the like can be incorporated asrequired.

Where administered intravenously, suitable carriers includephysiological saline, phosphate buffered saline (PBS), and solutionscontaining thickening and solubilizing agents such as glucose,polyethylene glycol, polypropyleneglycol, and mixtures thereof.Liposomal suspensions including tissue-targeted liposomes may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known for example, as described in U.S. Pat. No.4,522,811.

The active compounds may be prepared with carriers that protect thecompound against rapid elimination from the body, such as time-releaseformulations or coatings. Such carriers include controlled releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid, and the like.Methods for preparation of such formulations are known to those skilledin the art.

The compounds of the invention can be administered orally, parenternally(IV, IM, depo-IM, SQ, and depo-SQ), sublingually, intranasally(inhalation), intrathecally, topically, or rectally. Dosage forms knownto those skilled in the art are suitable for delivery of the compoundsof the invention.

Compounds of the invention may be administered enterally orparenterally. When administered orally, compounds of the invention canbe administered in usual dosage forms for oral administration as is wellknown to those skilled in the art. These dosage forms include the usualsolid unit dosage forms of tablets and capsules as well as liquid dosageforms such as solutions, suspensions, and elixirs. When the solid dosageforms are used, it is preferred that they be of the sustained releasetype so that the compounds of the invention need to be administered onlyonce or twice daily.

The oral dosage forms are administered to the patient 1, 2, 3, or 4times daily. It is preferred that the compounds of the invention beadministered either three or fewer times, more preferably once or twicedaily. Hence, it is preferred that the compounds of the invention beadministered in oral dosage form. It is preferred that whatever oraldosage form is used, that it be designed so as to protect the compoundsof the invention from the acidic environment of the stomach. Entericcoated tablets are well known to those skilled in the art. In addition,capsules filled with small spheres each coated to protect from theacidic stomach, are also well known to those skilled in the art.

When administered orally, an administered amount therapeuticallyeffective to inhibit beta-secretase activity, to inhibit A betaproduction, to inhibit A beta deposition, or to treat or prevent AD isfrom about 0.1 mg/day to about 1,000 mg/day. It is preferred that theoral dosage is from about 1 mg/day to about 100 mg/day. It is morepreferred that the oral dosage is from about 5 mg/day to about 50mg/day. It is understood that while a patient may be started at onedose, that dose may be varied over time as the patient's conditionchanges.

Compounds of the invention may also be advantageously delivered in anano crystal dispersion formulation. Preparation of such formulations isdescribed, for example, in U.S. Pat. No. 5,145,684. Nano crystallinedispersions of HIV protease inhibitors and their method of use aredescribed in U.S. Pat. No. 6,045,829. The nano crystalline formulationstypically afford greater bioavailability of drug compounds.

The compounds of the invention can be administered parenterally, forexample, by IV, IM, depo-IM, SC, or depo-SC. When administeredparenterally, a therapeutically effective amount of about 0.5 to about100 mg/day, preferably from about 5 to about 50 mg daily should bedelivered. When a depot formulation is used for injection once a monthor once every two weeks, the dose should be about 0.5 mg/day to about 50mg/day, or a monthly dose of from about 15 mg to about 1,500 mg. In partbecause of the forgetfulness of the patients with Alzheimer's disease,it is preferred that the parenteral dosage form be a depo formulation.

The compounds of the invention can be administered sublingually. Whengiven sublingually, the compounds of the invention should be given oneto four times daily in the amounts described above for IMadministration.

The compounds of the invention can be administered intranasally. Whengiven by this route, the appropriate dosage forms are a nasal spray ordry powder, as is known to those skilled in the art. The dosage of thecompounds of the invention for intranasal administration is the amountdescribed above for IM administration.

The compounds of the invention can be administered intrathecally. Whengiven by this route the appropriate dosage form can be a parenternaldosage form as is known to those skilled in the art. The dosage of thecompounds of the invention for intrathecal administration is the amountdescribed above for IM administration.

The compounds of the invention can be administered topically. When givenby this route, the appropriate dosage form is a cream, ointment, orpatch. Because of the amount of the compounds of the invention to beadministered, the patch is preferred. When administered topically, thedosage is from about 0.5 mg/day to about 200 mg/day. Because the amountthat can be delivered by a patch is limited, two or more patches may beused. The number and size of the patch is not important, what isimportant is that a therapeutically effective amount of the compounds ofthe invention be delivered as is known to those skilled in the art. Thecompounds of the invention can be administered rectally by suppositoryas is known to those skilled in the art. When administered bysuppository, the therapeutically effective amount is from about 0.5 mgto about 500 mg.

The compounds of the invention can be administered by implants as isknown to those skilled in the art. When administering a compound of theinvention by implant, the therapeutically effective amount is the amountdescribed above for depot administration.

The invention here is the new compounds of the invention and new methodsof using the compounds of the invention. Given a particular compound ofthe invention and a desired dosage form, one skilled in the art wouldknow how to prepare and administer the appropriate dosage form.

The compounds of the invention are used in the same manner, by the sameroutes of administration, using the same pharmaceutical dosage forms,and at the same dosing schedule as described above, for preventingdisease or treating patients with MCI (mild cognitive impairment) andpreventing or delaying the onset of Alzheimer's disease in those whowould progress from MCI to AD, for treating or preventing Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, and diffuse Lewy body type of Alzheimer's disease.

The compounds of the invention can be used in combination, with eachother or with other therapeutic agents or approaches used to treat orprevent the conditions listed above. Such agents or approaches include:acetylcholine esterase inhibitors such as tacrine(tetrahydroaminoacridine, marketed as COGNEX®), donepezil hydrochloride,(marketed as Aricept® and rivastigmine (marketed as Exelon®);gamma-secretase inhibitors; anti-inflammatory agents such ascyclooxygenase II inhibitors; anti-oxidants such as Vitamin E andginkolides; immunological approaches, such as, for example, immunizationwith A beta peptide or administration of anti-A beta peptide antibodies;statins; and direct or indirect neurotropic agents such asCerebrolysin®, AIT-082 (Emilieu, 2000, Arch. Neurol. 57:454), and otherneurotropic agents of the future.

It should be apparent to one skilled in the art that the exact dosageand frequency of administration will depend on the particular compoundsof the invention administered, the particular condition being treated,the severity of the condition being treated, the age, weight, generalphysical condition of the particular patient, and other medication theindividual may be taking as is well known to administering physicianswho are skilled in this art.

Inhibition of APP Cleavage

The compounds of the invention inhibit cleavage of APP between Met595and Asp596 numbered for the APP695 isoform, or a mutant thereof, or at acorresponding site of a different isoform, such as APP751 or APP770, ora mutant thereof (sometimes referred to as the “beta secretase site”).While not wishing to be bound by a particular theory, inhibition ofbeta-secretase activity is thought to inhibit production of beta amyloidpeptide (A beta). Inhibitory activity is demonstrated in one of avariety of inhibition assays, whereby cleavage of an APP substrate inthe presence of a beta-secretase enzyme is analyzed in the presence ofthe inhibitory compound, under conditions normally sufficient to resultin cleavage at the beta-secretase cleavage site. Reduction of APPcleavage at the beta-secretase cleavage site compared with an untreatedor inactive control is correlated with inhibitory activity. Assaysystems that can be used to demonstrate efficacy of the compoundinhibitors of the invention are known. Representative assay systems aredescribed, for example, in U.S. Pat. No. 5,942,400, 5,744,346, as wellas in the Examples below.

The enzymatic activity of beta-secretase and the production of A betacan be analyzed in vitro or in vivo, using natural, mutated, and/orsynthetic APP substrates, natural, mutated, and/or synthetic enzyme, andthe test compound. The analysis may involve primary or secondary cellsexpressing native, mutant, and/or synthetic APP and enzyme, animalmodels expressing native APP and enzyme, or may utilize transgenicanimal models expressing the substrate and enzyme. Detection ofenzymatic activity can be by analysis of one or more of the cleavageproducts, for example, by immunoassay, flurometric or chromogenic assay,HPLC, or other means of detection. Inhibitory compounds are determinedas those having the ability to decrease the amount of beta-secretasecleavage product produced in comparison to a control, wherebeta-secretase mediated cleavage in the reaction system is observed andmeasured in the absence of inhibitory compounds.

Beta-secretase

Various forms of beta-secretase enzyme are known, and are available anduseful for assay of enzyme activity and inhibition of enzyme activity.These include native, recombinant, and synthetic forms of the enzyme.Human beta-secretase is known as Beta Site APP Cleaving Enzyme (BACE),Asp2, and memapsin 2, and has been characterized, for example, in U.S.Pat. No. 5,744,346 and published PCT patent applications WO98/22597,WO/00/03819, WO01/23533, and WO/0017369, as well as in literaturepublications (Hussain et.al., 1999, Mol.Cell.Neurosci. 14:419–427;Vassar et.al., 1999, Science 286:735–741; Yan et.al., 1999, Nature402:533–537; Sinha et.al., 1999, Nature 40:537–540; and Lin et.al.,2000, PNAS USA 97:1456–1460). Synthetic forms of the enzyme have alsobeen described (WO98/22597 and WO00/17369). Beta-secretase can beextracted and purified from human brain tissue and can be produced incells, for example mammalian cells expressing recombinant enzyme.

Useful inhibitory compounds are effective to inhibit 50% ofbeta-secretase enzymatic activity at a concentration of less than 50micromolar, preferably at a concentration of 10 micromolar or less, morepreferably 1 micromolar or less, and most preferably 10 nanomolar orless.

APP Substrate

Assays that demonstrate inhibition of beta-secretase-mediated cleavageof APP can utilize any of the known forms of APP, including the 695amino acid “normal” isotype described by Kang et.al., 1987, Nature325:733–6, the 770 amino acid isotype described by Kitaguchi et. al.,1981, Nature 331:530–532, and variants such as the Swedish Mutation(KM670-1NL) (APP-SW), the London Mutation (V7176F), and others. See, forexample, U.S. Pat. No. 5,766,846 and also Hardy, 1992, Nature Genet.1:233–234, for a review of known variant mutations. Additional usefulsubstrates include the dibasic amino acid modification, APP-KKdisclosed, for example, in WO 00/17369, fragments of APP, and syntheticpeptides containing the beta-secretase cleavage site, wild type (WT) ormutated form, e.g., SW, as described, for example, in U.S. Pat. No5,942,400 and WO/00/03819.

The APP substrate contains the beta-secretase cleavage site of APP(KM-DA or NL-DA) for example, a complete APP peptide or variant, an APPfragment, a recombinant or synthetic APP, or a fusion peptide.Preferably, the fusion peptide includes the beta-secretase cleavage sitefused to a peptide having a moiety useful for enzymatic assay, forexample, having isolation and/or detection properties. A useful moietymay be an antigenic epitope for antibody binding, a label or otherdetection moiety, a binding substrate, and the like.

Antibodies

Products characteristic of APP cleavage can be measured by immunoassayusing various antibodies, as described, for example, in Pirttila et.al.,1999, Neuro.Lett. 249:21–4, and in U.S. Pat. No. 5,612,486. Usefulantibodies to detect A beta include, for example, the monoclonalantibody 6E10 (Senetek, St. Louis, Mo.) that specifically recognizes anepitope on amino acids 1–16 of the A beta peptide; antibodies 162 and164 (New York State Institute for Basic Research, Staten Island, N.Y.)that are specific for human A beta 1-40 and 1-42, respectively; andantibodies that recognize the junction region of beta-amyloid peptide,the site between residues 16 and 17, as described in U.S. Pat. No.5,593,846. Antibodies raised against a synthetic peptide of residues 591to 596 of APP and SW192 antibody raised against 590–596 of the Swedishmutation are also useful in immunoassay of APP and its cleavageproducts, as described in U.S. Pat. Nos. 5,604,102 and 5,721,130.

Assay Systems

Assays for determining APP cleavage at the beta-secretase cleavage siteare well known in the art. Exemplary assays, are described, for example,in U.S. Pat. Nos. 5,744,346 and 5,942,400, and described in the Examplesbelow.

Cell Free Assays

Exemplary assays that can be used to demonstrate the inhibitory activityof the compounds of the invention are described, for example, inWO00/17369, WO 00/03819, and U.S. Pat. Nos. 5,942,400 and 5,744,346.Such assays can be performed in cell-free incubations or in cellularincubations using cells expressing a beta-secretase and an APP substratehaving a beta-secretase cleavage site.

An APP substrate containing the beat-secretase cleavage site of APP, forexample, a complete APP or variant, an APP fragment, or a recombinant orsynthetic APP substrate containing the amino acid sequence: KM-DA orNL-DA, is incubated in the presence of beta-secretase enzyme, a fragmentthereof, or a synthetic or recombinant polypeptide variant havingbeta-secretase activity and effective to cleave the beta-secretasecleavage site of APP, under incubation conditions suitable for thecleavage activity of the enzyme. Suitable substrates optionally includederivatives that may be fusion proteins or peptides that contain thesubstrate peptide and a modification useful to facilitate thepurification or detection of the peptide or its beta-secretase cleavageproducts. Useful modifications include the insertion of a knownantigenic epitope for antibody binding; the linking of a label ordetectable moiety, the linking of a binding substrate, and the like.

Suitable incubation conditions for a cell-free in vitro assay include,for example: approximately 200 nanomolar to 10 micromolar substrate,approximately 10 to 200 picomolar enzyme, and approximately 0.1nanomolar to 10 micromolar inhibitor compound, in aqueous solution, atan approximate pH of 4–7, at approximately 37 degrees C., for a timeperiod of approximately 10 minutes to 3 hours. These incubationconditions are exemplary only, and can be varied as required for theparticular assay components and/or desired measurement system.Optimization of the incubation conditions for the particular assaycomponents should account for the specific beta-secretase enzyme usedand its pH optimum, any additional enzymes and/or markers that might beused in the assay, and the like. Such optimization is routine and willnot require undue experimentation.

One useful assay utilizes a fusion peptide having maltose bindingprotein (MBP) fused to the C-terminal 125 amino acids of APP-SW. The MBPportion is captured on an assay substrate by anti-MBP capture antibody.Incubation of the captured fusion protein in the presence ofbeta-secretase results in cleavage of the substrate at thebeta-secretase cleavage site. Analysis of the cleavage activity can be,for example, by immunoassay of cleavage products. One such immunoassaydetects a unique epitope exposed at the carboxy terminus of the cleavedfusion protein, for example, using the antibody SW192. This assay isdescribed, for example, in U.S. Pat. No 5,942,400.

Cellular Assay

Numerous cell-based assays can be used to analyze beta-secretaseactivity and/or processing of APP to release A beta. Contact of an APPsubstrate with a beta-secretase enzyme within the cell and in thepresence or absence of a compound inhibitor of the invention can be usedto demonstrate beta-secretase inhibitory activity of the compound.Preferably, assay in the presence of a useful inhibitory compoundprovides at least about 30%, most preferably at least about 50%inhibition of the enzymatic activity, as compared with a non-inhibitedcontrol.

In one embodiment, cells that naturally express beta-secretase are used.Alternatively, cells are modified to express a recombinantbeta-secretase or synthetic variant enzyme as discussed above. The APPsubstrate may be added to the culture medium and is preferably expressedin the cells. Cells that naturally express APP, variant or mutant formsof APP, or cells transformed to express an isoform of APP, mutant orvariant APP, recombinant or synthetic APP, APP fragment, or syntheticAPP peptide or fusion protein containing the beta-secretase APP cleavagesite can be used, provided that the expressed APP is permitted tocontact the enzyme and enzymatic cleavage activity can be analyzed.

Human cell lines that normally process A beta from APP provide a usefulmeans to assay inhibitory activities of the compounds of the invention.Production and release of A beta and/or other cleavage products into theculture medium can be measured, for example by immunoassay, such asWestern blot or enzyme-linked immunoassay (EIA) such as by ELISA.

Cells expressing an APP substrate and an active beta-secretase can beincubated in the presence of a compound inhibitor to demonstrateinhibition of enzymatic activity as compared with a control. Activity ofbeta-secretase can be measured by analysis of one or more cleavageproducts of the APP substrate. For example, inhibition of beta-secretaseactivity against the substrate APP would be expected to decrease releaseof specific beta-secretase induced APP cleavage products such as A beta.

Although both neural and non-neural cells process and release A beta,levels of endogenous beta-secretase activity are low and often difficultto detect by EIA. The use of cell types known to have enhancedbeta-secretase activity, enhanced processing of APP to A beta, and/orenhanced production of A beta are therefore preferred. For example,transfection of cells with the Swedish Mutant form of APP (APP-SW); withAPP-KK; or with APP-SW-KK provides cells having enhanced beta-secretaseactivity and producing amounts of A beta that can be readily measured.

In such assays, for example, the cells expressing APP and beta-secretaseare incubated in a culture medium under conditions suitable forbeta-secretase enzymatic activity at its cleavage site on the APPsubstrate. On exposure of the cells to the compound inhibitor, theamount of A beta released into the medium and/or the amount of CTF99fragments of APP in the cell lysates is reduced as compared with thecontrol. The cleavage products of APP can be analyzed, for example, byimmune reactions with specific antibodies, as discussed above.

Preferred cells for analysis of beta-secretase activity include primaryhuman neuronal cells, primary transgenic animal neuronal cells where thetransgene is APP, and other cells such as those of a stable 293 cellline expressing APP, for example, APP-SW.

In Vivo Assays: Animal Models

Various animal models can be used to analyze beta-secretase activity and/or processing of APP to release A beta, as described above. Forexample, transgenic animals expressing APP substrate and beta-secretaseenzyme can be used to demonstrate inhibitory activity of the compoundsof the invention. Certain transgenic animal models have been described,for example, in U.S. Pat. Nos. 5,877,399; 5,612,486; 5,387,742;5,720,936; 5,850,003; 5,877,015,, and 5,811,633, and in Ganes et.al.,1995, Nature 373:523. Preferred are animals that exhibit characteristicsassociated with the pathophysiology of AD. Administration of thecompound inhibitors of the invention to the transgenic mice describedherein provides an alternative method for demonstrating the inhibitoryactivity of the compounds. Administration of the compounds in apharmaceutically effective carrier and via an administrative route thatreaches the target tissue in an appropriate therapeutic amount is alsopreferred.

Inhibition of beta-secretase mediated cleavage of APP at thebeta-secretase cleavage site and of A beta release can be analyzed inthese animals by measure of cleavage fragments in the animal's bodyfluids such as cerebral fluid or tissues. Analysis of brain tissues forA beta deposits or plaques is preferred.

On contacting an APP substrate with a beta-secretase enzyme in thepresence of an inhibitory compound of the invention and under conditionssufficient to permit enzymatic mediated cleavage of APP and/or releaseof A beta from the substrate, the compounds of the invention areeffective to reduce beta-secretase-mediated cleavage of APP at thebeta-secretase cleavage site and/or effective to reduce released amountsof A beta. Where such contacting is the administration of the inhibitorycompounds of the invention to an animal model, for example, as describedabove, the compounds are effective to reduce A beta deposition in braintissues of the animal, and to reduce the number and/or size of betaamyloid plaques. Where such administration is to a human subject, thecompounds are effective to inhibit or slow the progression of diseasecharacterized by enhanced amounts of A beta, to slow the progression ofAD in the, and/or to prevent onset or development of AD in a patient atrisk for the disease.

Unless defined otherwise, all scientific and technical terms used hereinhave the same meaning as commonly understood by one of skill in the artto which this invention belongs. All patents and publications referredto herein are hereby incorporated by reference for all purposes.

DEFINITIONS AND CONVENTIONS

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

I. Conventions for Formulas and Definitions of Variables

The chemical formulas representing various compounds or molecularfragments in the specification and claims may contain variablesubstituents in addition to expressly defined structural features. Thesevariable substituents are identified by a letter or a letter followed bya numerical subscript, for example, “Z₁” or “R_(i)” where “i” is aninteger. These variable substituents are either monovalent or bivalent,that is, they represent a group attached to the formula by one or twochemical bonds. For example, a group Z₁ would represent a bivalentvariable if attached to the formula CH₃—C(═Z₁)H. Groups R_(i) and R_(j)would represent monovalent variable substituents if attached to theformula CH₃—CH₂—C(R_(i))(R_(j))H₂. When chemical formulas are drawn in alinear fashion, such as those above, variable substituents contained inparentheses are bonded to the atom immediately to the left of thevariable substituent enclosed in parentheses. When two or moreconsecutive variable substituents are enclosed in parentheses, each ofthe consecutive variable substituents is bonded to the immediatelypreceding atom to the left which is not enclosed in parentheses. Thus,in the formula above, both R_(i) and R_(j) are bonded to the precedingcarbon atom. Also, for any molecule with an established system of carbonatom numbering, such as steroids, these carbon atoms are designated asC_(i), where “i” is the integer corresponding to the carbon atom number.For example, C₆ represents the 6 position or carbon atom number in thesteroid nucleus as traditionally designated by those skilled in the artof steroid chemistry. Likewise the term “R₆” represents a variablesubstituent (either monovalent or bivalent) at the C₆ position.

Chemical formulas or portions thereof drawn in a linear fashionrepresent atoms in a linear chain. The symbol “—” in general representsa bond between two atoms in the chain. Thus CH₃—O—CH₂—CH(R_(i))—CH₃represents a 2-substituted-1-methoxypropane compound. In a similarfashion, the symbol “═” represents a double bond, e.g.,CH₂═C(R_(i))—O—CH₃, and the symbol “≡” represents a triple bond, e.g.,HC≡C—CH(R_(i))—CH₂—CH₃. Carbonyl groups are represented in either one oftwo ways: —CO— or —C(═O)—, with the former being preferred forsimplicity.

Chemical formulas of cyclic (ring) compounds or molecular fragments canbe represented in a linear fashion. Thus, the compound4-chloro-2-methylpyridine can be represented in linear fashion byN*═C(CH₃)—CH═CCl—CH═C*H with the convention that the atoms marked withan asterisk (*) are bonded to each other resulting in the formation of aring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinylcan be represented by —N*—(CH₂)₂—N(C₂H₅)—CH₂—C*H₂.

A rigid cyclic (ring) structure for any compounds herein defines anorientation with respect to the plane of the ring for substituentsattached to each carbon atom of the rigid cyclic compound. For saturatedcompounds which have two substituents attached to acarbon atom which ispart of a cyclic system, —C(X₁)(X₂)— the two substituents may be ineither an axial or equatorial position relative to the ring and maychange between axial/equatorial. However, the position of the twosubstituents relative to the ring and each other remains fixed. Whileeither substituent at times may lie in the plane of the ring(equatorial) rather than above or below the plane (axial), onesubstituent is always above the other. In chemical structural formulasdepicting such compounds, a substituent (X₁) which is “below” anothersubstituent (X₂) will be identified as being in the alpha configurationand is identified by a broken, dashed or dotted line attachment to thecarbon atom, i.e., by the symbol “ - - - ” or “ . . . ”. Thecorresponding substituent attached “above” (X₂) the other (X₁) isidentified as being in the beta configuration and is indicated by anunbroken line attachment to the carbon atom.

When a variable substituent is bivalent, the valences may be takentogether or separately or both in the definition of the variable. Forexample, a variable R_(i) attached to a carbon atom as —C(═R₁)— might bebivalent and be defined as oxo or keto (thus forming a carbonyl group(—CO—) or as two separately attached monovalent variable substituentsalpha-R_(i-j) and beta-R_(i-k). When a bivalent variable, R_(i), isdefined to consist of two monovalent variable substituents, theconvention used to define the bivalent variable is of the form“alpha-R_(i-j):beta-R_(i-k)” or some variant thereof. In such a caseboth alpha-R_(i-j) and beta-R_(i-k) are attached to the carbon atom togive —C(alpha-R_(i-j))(beta-R_(i-k))—. For example, when the bivalentvariable R₆, —C(═R₆)— is defined to consist of two monovalent variablesubstituents, the two monovalent variable substituents arealpha-R₆₋₁:beta-R₆₋₂, . . . alpha-R₆₋₉:beta-R₆₋₁₀, etc, giving—C(alpha-R₆₋₁)(beta-R₆₋₂)—, . . . —C(alpha-R₆₋₉)(beta-R₆₋₁₀)—, etc.Likewise, for the bivalent variable R₁₁, —C(═R₁₁)—, two monovalentvariable substituents are alpha-R₁₁₋₁:beta-R₁₁₋₂. For a ring substituentfor which separate alpha and beta orientations do not exist (e.g. due tothe presence of a carbon carbon double bond in the ring), and for asubstituent bonded to a carbon atom which is not part of a ring theabove convention is still used, but the alpha and beta designations areomitted.

Just as a bivalent variable may be defined as two separate monovalentvariable substituents, two separate monovalent variable substituents maybe defined to be taken together to form a bivalent variable. Forexample, in the formula —C₁(R_(i))H—C₂(R_(j))H— (C₁ and C₂ definearbitrarily a first and second carbon atom, respectively) R_(i) andR_(j) may be defined to be taken together to form (1) a second bondbetween C₁ and C₂ or (2) a bivalent group such as oxa (—O—) and theformula thereby describes an epoxide. When R_(i) and R_(j) are takentogether to form a more complex entity, such as the group —X—Y—, thenthe orientation of the entity is such that C, in the above formula isbonded to X and C₂ is bonded to Y. Thus, by convention the designation “. . . R_(i) and R_(j) are taken together to form —CH₂—CH₂—O—CO— . . . ”means a lactone in which the carbonyl is bonded to C₂. However, whendesignated “ . . . R_(j) and R_(i) are taken together to form—CO—O—CH₂—CH₂— the convention means a lactone in which the carbonyl isbonded to C₁.

The carbon atom content of variable substituents is indicated in one oftwo ways. The first method uses a prefix to the entire name of thevariable such as “C₁–C₄”, where both “1” and “4” are integersrepresenting the minimum and maximum number of carbon atoms in thevariable. The prefix is separated from the variable by a space. Forexample, “C₁–C₄ alkyl” represents alkyl of 1 through 4 carbon atoms,(including isomeric forms thereof unless an express indication to thecontrary is given). Whenever this single prefix is given, the prefixindicates the entire carbon atom content of the variable being defined.Thus C₂–C₄ alkoxycarbonyl describes a group CH₃—(CH₂)_(n)—O—CO— where nis zero, one or two. By the second method the carbon atom content ofonly each portion of the definition is indicated separately by enclosingthe “C_(i)–C_(j)” designation in parentheses and placing it immediately(no intervening space) before the portion of the definition beingdefined. By this optional convention (C₁–C₃)alkoxycarbonyl has the samemeaning as C₂–C₄ alkoxycarbonyl because the “C₁–C₃” refers only to thecarbon atom content of the alkoxy group. Similarly while both C₂–C₆alkoxyalkyl and (C₁–C₃)alkoxy(C₁–C₃)alkyl define alkoxyalkyl groupscontaining from 2 to 6 carbon atoms, the two definitions differ sincethe former definition allows either the alkoxy or alkyl portion alone tocontain 4 or 5 carbon atoms while the latter definition limits either ofthese groups to 3 carbon atoms.

When the claims contain a fairly complex (cyclic) substituent, at theend of the phrase naming/designating that particular substituent will bea notation in (parentheses) which will correspond to the samename/designation in one of the CHARTS which will also set forth thechemical structural formula of that particular substituent.

II. Definitions

All temperatures are in degrees Celsius.

TLC refers to thin-layer chromatography.

psi refers to pounds/in².

HPLC refers to high pressure liquid chromatography.

THF refers to tetrahydrofuran.

DMF refers to dimethylformamide.

EDC refers to ethyl-1-(3-dimethylaminopropyl)carbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

HOBt refers to 1-hydroxy benzotriazole hydrate.

NMM refers to N-methylmorpholine.

NBS refers to N-bromosuccinimide.

TEA refers to triethylamine.

BOC refers to 1,1-dimethylethoxy carbonyl or t-butoxycarbonyl,—CO—O—C(CH₃)₃.

CBZ refers to benzyloxycarbonyl, —CO—O—CH₂-phenyl.

FMOC refers to 9-fluorenylmethyl carbonate.

TFA refers to trifluoracetic acid, CF₃—COOH.

CDI refers to 1,1′-carbonyldiimidazole.

Saline refers to an aqueous saturated sodium chloride solution.

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts arereported in ppm (δ) downfield from TMS.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (d) downfield from TMS.

IR refers to infrared spectroscopy.

-phenyl refers to phenyl (C₆H₅).

MS refers to mass spectrometry expressed as m/e, m/z or mass/chargeunit. MH⁺ refers to the positive ion of a parent plus a hydrogen atom.EI refers to electron impact. CI refers to chemical ionization. FABrefers to fast atom bombardment.

HRMS refers to high resolution mass spectrometry.

Ether refers to diethyl ether.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to the solvent is weight/volume (wt/v).

BOP refers to benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate.

TBDMSCl refers to t-butyldimethylsilyl chloride.

TBDMSOTf refers to t-butyldimethylsilyl trifluosulfonic acid ester.

Trisomy 21 refers to Down's Syndrome.

The following terms are used (in EXAMPLEs 321 and above) for the amideforming agent (IX):

“PHTH” refers to (CH₃—CH₂—CH₂—)₂N—CO-phenyl-CO—OH where the attachmentto the -phenyl-ring is 1,3-;

“5-Me-PHTH” refers to (CH₃—CH₂—CH₂—)₂N—CO—(CH₃—) phenyl —CO—OH where theattachment to the -phenyl-ring is 1,3- for the carbonyl groups and 5-for the methyl group;

“3,5-pyridinyl” refers to (CH₃—CH₂—CH₂—)₂N—CO—(pyridinyl) —CO—OH wherethe attachment to the -pyridinyl-ring is 3,5- for the carbonyl groups;

“—SO₂—” refers to (CH₃—CH₂—CH₂—)₂CH-SO₂-phenyl —CO—OH where theattachment to the -phenyl-ring is 1,3-;

“5-OMe-PHTH” refers to (CH₃—CH₂—CH₂—)₂N—CO—(CH₃—O—) phenyl- CO—OH wherethe attachment to the -phenyl-ring is 1,3- for the carbonyl groups and5- for the methoxy group;

“5–C₁-PHTH” refers to (CH₃—CH₂—CH₂—)₂N—CO—(Cl—)phenyl-CO—OH where theattachment to the -phenyl-ring is 1,3- for the carbonyl groups and 5-for the chlorine atom;

“5-F-PHTH” refers to (CH₃—CH₂—CH₂—)₂N—CO—(F—)phenyl-CO—OH where theattachment to the -phenyl-ring is 1,3- for the carbonyl groups and 5-for the fluorine atom;

“thienyl” refers to (CH₃—CH₂—CH₂—)₂N—CO-thienyl-CO—OH where theattachment to the thiophene ring is -2,5;

“2,4-pyridinyl” refers to (CH₃—CH₂—CH₂—)₂N—CO—(pyridinyl) —CO—OH wherethe attachment to the -pyridinyl-ring is 2,4- for the carbonyl groups;

“4,6-pyrimidinyl” refers to(CH₃—CH₂—CH₂—)₂N—CO—(pyrimidinyl-)phenyl-CO—OH where the attachment tothe -pyrimidiny-l ring is 4,6- for the carbonyl groups;

“morpholinyl” refers to morpholinyl-CO-phenyl-CO—OH where the attachmentto the -phenyl-ring is 1,3 for the carbonyl groups.

APP, amyloid precursor protein, is defined as any APP polypeptide,including APP variants, mutations, and isoforms, for example, asdisclosed in U.S. Pat. No. 5,766,846.

A beta, amyloid beta peptide, is defined as any peptide resulting frombeta-secretase mediated cleavage of APP, including peptides of 39, 40,41, 42, and 43 amino acids, and extending from the beta-secretasecleavage site to amino acids 39, 40, 41, 42, or 43.

Beta-secretase (BACE1, Asp2, Memapsin 2) is an aspartyl protease thatmediates cleavage of APP at the amino-terminal edge of A beta. Humanbeta-secretase is described, for example, in WO/0017369.

“Pharmaceutically acceptable” refers to those properties and/orsubstances that are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

A therapeutically effective amount is defined as an amount effective toreduce or lessen at least one symptom of the disease being treated or toreduce or delay onset of one or more clinical markers or symptoms of thedisease.

The present invention provides compounds, compositions, and methods forinhibiting beta-secretase enzyme activity and A beta peptide production.Inhibition of beta-secretase enzyme activity halts or reduces theproduction of A beta from APP and reduces or eliminates the formation ofbeta-amyloid deposits in the brain.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

Preparation 1 3-Amino-5-(methoxycarbonyl)benzoic acid (XVII)

A suspension of mono-methyl 5-nitro-isophthalate (22.5 g, 100 mmol) andpalladium on carbon (5%, 2.00 g) in methanol (100 mL) is shaken in ahydrogenation apparatus under hydrogen (50 psi) for 3 hours. The mixtureis then filtered through diatomaceous earth and concentrated to give thetitle compound, NMR (300 MHz, CDCl₃) delta 7.67, 7.41, 7.40 and 3.83; MS(ESI−) for C₉H₉NO₄ m/z (M−H)⁻=194.

Preparation 2 3-Bromo-5-(methoxycarbonyl)benzoic acid (XIX)

A mixture of copper (II) bromide (1.85 g, 8.30 mmol), n-butyl nitrite(1.07 g, 10.4 mmol), and acetonitrile (30 mL) is stirred in a roundbottomed flask in a water bath to which a few chunks of ice has beenadded. 3-Amino-5-(methoxycarbonyl)benzoic acid (XVII, PREPARATION 1,1.35 g, 6.92 mmol) is added as a slurry in warm acetonitrile (70 mL)over 15 min and the mixture is stirred at 20–25 degrees C. for anadditional 2 hour, at which time the mixture is partitioned betweendichloromethane and hydrochloric acid (3N). The organic phase isseparated and dried over sodium sulfate and concentrated to dryness.Chromatography (silica gel, 125 mL; methanol/dichloromethane, 15/85) andconcentration of the appropriate fractions gives a solid which iscrystallized from methanol to give the title compound in two crops, NMR(DMSO-d₆) delta 3.90, 8.26 and 8.65.

Preparation 3 Methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (XXI)

Carbonyl diimidazole (3–0 g, 18 mmol) is added to a solution of3-bromo-5-(methoxycarbonyl)benzoic acid (XIX, PREPARATION 2, 3.9 g, 15mmol) in THF (30 mL). The mixture is stirred for 0.5 hours.Dipropylamine (AMINE, 4.2 mL, 30 mmol) is added to the mixture, which isthen stirred for 24 hours. The solvent is then removed under reducedpressure and the mixture is partitioned between ethyl acetate and water.The organic phase is then washed with saline, dried over anhydrousmagnesium sulfate, filtered, and concentrated. Column chromatography(silica gel; ethyl acetate/hexanes, 15/85) gives the title compound, IR(diffuse reflectance) 2968, 2958, 1714, 1637, 1479, 1440, 1422, 1321,1310, 1288, 1273, 1252, 889, 772 and 718 cm⁻¹; NMR (300 MHz, CDCl₃) δ8.21, 7.96, 7.70, 3.95, 3.46, 3.15, 1.69, 1.57, 1.00 and 0.78; MS (ESI+)for C₁₅H₂₀BrNO₃ m/z (M+H)⁺=344.1.

Preparation 4 3-Bromo-5-[(dipropylamino)carbonyl]benzoic acid

To a solution of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate(XXI, PREPARATION 3, 1.4 g, 4.1 mmol) in THF/water/methanol (4/2/2, 8mL) is added to lithium hydroxide monohydrate (0.17 g, 4.05 mmol). Themixture is stirred at 20 degrees −25 degrees C. for 1 hour and thensolvent is removed under reduced pressure. The residue is dissolved inwater (50 mL) and hydrochloric acid (1 N) is added to adjust the pH toabout 3. The aqueous mixture is extracted with ethyl acetate and theorganic phase is separated and dried over magnesium sulfate to give thetitle compound. Analytical calculated for C₁₄H₁₈BrNO₃: C, 51.23;H, 5.53;N, 4.27; Br, 24.35. Found: C, 51.37;H, 5.56; N, 4.28.

Preparation 5 Methyl3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]-benzoate (XXII)

To a mixture of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (XXI,PREPARATION 3, 0.5 g, 1.47 mmol) in dry N-methyl pyrrolidinone under acarbon monoxide atmosphere is added palladium (II) acetate (0.017 g,0.074 mmol), 1,3-bis(diphenylphosphino)propane (0.045 g, 0.11 mmol),hexamethyldisilazane (1.0 mL, 4.7 mmol), and diisopropylethylamine (0.38g, 2.94 mmol). The mixture is heated at 100 degrees C. for 24 hours. Themixture is cooled to 20–25 degrees C. and partitioned between water andethyl acetate. The layers are separated and the aqueous phase isback-washed with ethyl acetate. The organic phases are combined andwashed three times with saline, dried over anhydrous magnesium sulfate,filtered and concentrated. Column chromatography (silica gel, 75 mL;methanol/methylene chloride, 2.5/97.5) gives the title compound, NMR(CDCl₃) delta 0.77, 1.02, 1.57, 1.71, 3.17, 3.49, 3.98, 5.78, 6.34,8.07, 8.20 and 8.48.

Preparation 6 3-(Aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoic acid(XXIII)

To a mixture of methyl3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoate (XXII, PREPARATION5, 0.197 g, 0.64 mmol) in methanol (5.0 mL) is added sodium hydroxide(1N, 3.0 mL). The mixture is stirred at 20–25 degrees C. for 24 hours.The mixture is acidified to about pH 5 with hydrochloric acid (10%).Water (50 mL) is added and the mixture is washed twice with ethylacetate (2×50 mL). The organic extracts are combined and dried overanhydrous magnesium sulfate and concentrated to give the title compound,NMR (DMSO-d₆) delta 0.66, 0.930, 1.48, 1.62, 3.12, 3.35, 7.54, 7.98,8.22 and 8.51.

Preparation 7 3-Cyano-5-[(dipropylamino)carbonyl]benzoic acid (IX/XXXII)

A mixture of 3-bromo-5-[(dipropylamino)carbonyl]benzoic acid(PREPARATION 4, 0.596 g, 1.82 mmol) and copper nitrile (0.325 g, 3.63mmol) in N-methylpyrrolidinone (1.5 mL) is stirred at 175 degrees C. for2.5 hour, at which time the mixture is cooled and partitioned betweenethyl acetate and hydrochloric acid (3N). The organic layer is washedtwice more with hydrochloric acid (3N) and then twice more with salinewhich had been acidified with a small amount of hydrochloric acid (3N).The organic layer is dried over magnesium sulfate and concentrated underhigh vacuum to give the title compound, NMR (CDCl₃) delta 0.80, 1.02,1.60, 1.73, 3.17, 3.51, 7.90, 8.31 and 8.41; an aliquot is crystallizedfrom ethyl ether/dichloromethane/hexane —IR (diffuse reflectance) 3017,2970, 2937, 2898, 2877, 2473, 2432, 2350, 2318, 2236, 1721, 1608, 1588,1206 and 1196 cm⁻¹.

Preparation 8 3-(Aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoic acid(XXXIII)

A mixture of 3-cyano-5-[(dipropylamino)carbonyl]benzoic acid (IX/XXXII,PREPARATION 7, 0.602 g, 2.19 mmol), potassium carbonate (0.212 g, 1.53mmol), and acetone (2.5 mL) is stirred at 20–25 degrees C. Water (2.5mL) and urea-hydrogen peroxide adduct (0.825 g, 8.78 mmol) are added andthe mixture is stirred for 15 hours at 20–25 degrees C., at which timeadditional urea-hydrogen peroxide adduct (0.204 g) is added; afterstirring for another 3 hours, an additional 0.205 g of urea-hydrogenperoxide is added. After a total of 39 hours has elapsed, the acetone isremoved under reduced pressure and the residue is acidified withhydrochloric acid (3N) to pH=2–4. The mixture is extracted withdichloromethane, the organic layer is separated and washed withhydrochloric acid (0.5 N), and the organic phase is dried with anhydrousmagnesium sulfate to a solid. The solid is crystallized fromdichloromethane/hexane/methanol to give the title compound, MS (ESI+)for C₁₅H₂₀N₂O₄ m/z (M+H)⁺=293.2.

Preparation 9 Methyl 3-[(dipropylamino)carbonyl]-5-nitrobenzoate (XXX)

Carbonyl diimidazole (3.90 g, 24.0 mmol) is added to a mixture ofmono-methyl 5-nitro-isophthalate (XXVIII, 4.50 g, 20.0 mmol) in dry THF(50 mL). The mixture is stirred for 0.5 hours. Dipropylamine (3.28 mL,24.0 mmol) is added slowly to the mixture. The reaction mixture is thenstirred for 4 hours. The solvent is removed under reduced pressure andthe mixture is partitioned between ethyl acetate and water. The organicphase is separated and washed with saline, dried over anhydrous sodiumsulfate, filtered, and concentrated. Column chromatography (silica gel;ethyl acetate/hexanes, 15/85) gives the title compound, NMR (300 MHz,CDCl₃) delta 8.88, 8.41, 8.35, 4.00, 3.48, 3.15, 1.72, 1.57, 1.00 and0.77; MS (ESI+) for C₁₅H₂₀N₂O₅ m/z (M+H)⁺=309.2.

Preparation 10 Methyl 3-amino-5-[(dipropylamino)carbonyl]Benzoate (XXXI)

A suspension of methyl 3-[(dipropylamino)carbonyl]-5-nitrobenzoate (XXX,PREPARATION 9, 6.00g, 20.0 mmol) and palladium on carbon (5%, 0.600 g)in methanol (40 mL) is shaken in a hydrogenation apparatus underhydrogen (45 psi) for 3 hours. The mixture is then filtered throughdiatomaceous earth and concentrated to give the title compound, NMR (300MHz, CDCl₃) delta 7.27, 6.77, 4.10, 3.82, 3.38, 3.10, 1.62, 1.46, 0.91and 0.68.

Preparation 11 Methyl3-(chlorosulfonyl)-5-[(dipropylamino)carbonyl]-Benzoate (XXXVII)

Methyl 3-amino-5-[(dipropylamino)carbonyl]benzoate (XXXI, PREPARATION10, 1.11 g, 4 mmol) is added to a mixture of water (5 mL) andconcentrated hydrochloric acid (1 mL). Sodium nitrite (0.276 g, 4 mmol)is added to the mixture slowly at 0 degrees C. The mixture is then addedto an acetic acid solution (5 mL) of CuCl₂.2H₂O saturated with sulfurdioxide. The mixture is stirred for 0.5 hours and poured into ice water.The mixture is extracted with ethyl acetate. The organic phase isseparated and washed with saturated sodium bicarbonate, water, andsaline and dried over anhydrous sodium sulfate, filtered, andconcentrated to give the title compound, NMR (300 MHz, CDCl₃) delta8.69, 8.38, 8.20,4.01, 3.49, 3.14, 1.72,1.59, 1.01 and 0.79; MS (ESI+)for C₁₅H₂₀ClNO₅S m/z (M+H)⁺=362.2.

Preparation 12 Methyl3-(aminosulfonyl)-5-[(dipropylamino)carbonyl]-benzoate (XXXVIII)

To a solution of methyl3-(chlorosulfonyl)-5-[(dipropylamino)carbonyl]benzoate (XXXVII,PREPARATION 11, 0.100 g, 0.300 mmol) in dry THF (3 mL) is added ammonia(7 N solution in methanol, 0.214 mL, 1.50 mmol). The mixture is stirredfor 18 hours and solvent is then removed. The residue is partitionedbetween ethyl acetate and water. The organic phase is separate andwashed with saline, dried over anhydrous sodium sulfate, filtered, andconcentrated to give the title compound, NMR (300 MHz, CDCl₃) delta8.45, 8.07, 8.01, 6.05, 3.93, 3.44, 3.09, 1.67, 1.52, 0.96 and 0.73; MS(ESI+) for C₁₂H₂₂N₂O₅S m/z (M+H)⁺=343.3.

Preparation 13 3-(Aminosulfonyl)-5-[(dipropylamino)carbonyl]benzoic acid(XXXVIII)

Lithium hydroxide monohydrate (0.011 g, 0.263 mmol) is added to asolution of methyl 3-(aminosulfonyl)-5-[(dipropylamino)carbonyl]benzoate(XXXVIII, PREPARATION 12, 0.090 g, 0.263 mmol) in a mixture ofTHF/methanol/water (2/1/1, 2 mL). The mixture is stirred at 20–25degrees C. for 3 hours. The mixture is then diluted with water andhydrochloric acid (1 N) is added to bring the pH to less than 3. Theaqueous solution is extracted with ethyl acetate. The organic phase isseparated and washed with saline, dried over anhydrous sodium sulfate,filtered and concentrated to give the title compound. ¹H NMR (300 MHz,CDCl₃) delta 10.36 (s, 1H), 8.39 (s, 1H), 8.09 (s, 2H), 6.06 (s, 2H),3.48 (t, J=7 Hz, 2H), 3.15 (t, J=7 Hz, 2H), 1.71 (m, 2H), 1.55 (m, 2H),0.97 (t, J=7 Hz, 31H), 0.74 (t, J=7 Hz, 3H). MS (ESI+) for C₁₁H₂₀N₂O₅Sm/z 329.2 (M+H)⁺.

Preparation 14 Methyl3-[(dipropylamino)carbonyl]-5-(1-pyrrolidinylsulfonyl)-benzoate(XXXVIII)

Following the general procedure of PREPARATION 12 and makingnon-critical variations but using pyrrolidine (0.347 mL, 4.16 mmol), thetitle compound is obtained, MS (ESI+) for C₁₉H₂₈N₂O₅S m/z (M+H)⁺=397.1.

Preparation 153-[(Dipropylamino)carbonyl]-5-(1-pyrrolidinylsulfonyl)benzoic acid(XXXIX)

Following the general procedure of PREPARATION 13 and makingnon-critical variations, the title compound is obtained, MS (ESI+) forC₁₈H₂₆N₂O₅S m/z (M+H)⁺=383.3.

Preparation 16 Methyl3-[(dipropylamino)carbonyl]-5-[(methylamino)-sulfonyl]benzoate (XXXVIII)

Following the general procedure of PREPARATION 12 and makingnon-critical variations but using methyl amine (2 N solution in THF,0.692 mL, 1.38 mmol), the title compound is obtained, MS (ESI+) forC₁₆H₂₄N₂O₅S m/z (M+H)⁺=357.1.

Preparation 173-[(Dipropylamino)carbonyl]-5-[(methylamino)-sulfonyl]benzoic acid(XXXIX)

Following the general procedure of PREPARATION 13 and makingnon-critical variations, the title compound is obtained, MS (ESI+) forC₁₅H₂₂N₂O₅S m/z (M+H)⁺=343. 1.

Preparation 18 Methyl3-[(dimethylamino)sulfonyl]-5-[(dipropylamino)-carbonyl]benzoate(XXXVIII)

Following the general procedure of PREPARATION 12 and makingnon-critical variations but using dimethylamine (2 N solution in THF,0.692 mL, 1.38 mmol), the title compound is obtained, MS (ESI+) forC₁₇H₂₆N₂O₅S m/z (M+H)₊=371.1.

Preparation 193-[(Dimethylamino)sulfonyl]-5-[(dipropylamino)carbonyl]-benzoic acid(XXXIX)

Following the general procedure of PREPARATION 13 and makingnon-critical variations, the title compound is obtained, MS (ESI+) forC₁₆H₂₄N₂O₅S m/z (M+H)⁺=357.1.

Preparation 20 Methyl ³-[(dipropylamino)carbonyl]-5-ethylbenzoate (IX)

Ethylboronic acid (0.800 g, 10.8 mmol),dichlorobis(triphenylphosphine)-palladium(II) (0.252 g, 0.360 mmol),potassium carbonate (2.50 g, 18.0 mmol) and lithium chloride (0.151 g,3.60 mmol) are added to a mixture of methyl3-bromo-5-[(dipropylamino)carbonyl]benzoate (1.23 g, 3.60 mmol) in dryDMF (20 mL). The mixture is heated at 100 degrees C. for 18 hours. Themixture is then partitioned between ethyl acetate and water. The phasesare separated and the ethyl acetate phase is washed with saline, driedover sodium sulfate and concentrated. The concentrate is columnchromatographed (silica gel; ethyl acetate/hexanes, 15/85) to give thetitle compound, MS (ESI+) for C₁₇H₂₅NO₃ m/z (M+H)⁺=292.2.

Preparation 21 3-[(Dipropylamino)carbonyl]-5-ethylbenzoic acid (IX)

Lithium hydroxide monohydrate (0.0680 g, 1.6 mmol) is added to a mixtureof methyl 3-[(dipropylamino)carbonyl]-5-ethylbenzoate (PREPARATION 20,0.450 g, 1.6 mmol) in a mixture of THF/methanol/water (2/1/1, 8 mL). Themixture is stirred at 20–25 degrees C. for 3 hours. The mixture is thendiluted with water (20 mL) and hydrochloric acid (1 N) is added to bringthe pH to less than 3. The aqueous mixture is extracted with ethylacetate. The organic phase is separated and washed with saline, driedover anhydrous magnesium sulfate, filtered and concentrated to give thetitle compound, MS (ESI+) for C₁₆H₂₃NO₃ m/z (M+H)⁺=278.2.

Example 1 tert-Butyl(1S)-3-bromo-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III)

N-methyl-morpholine (5.83 Ml, 53 mmole, 1.05 eq.) is added to(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid(II, 15 g, 50 mmole) in THF (100 mL) and the reaction is cooled to −78degrees C. Isobutyl chloroformate (6.87 mL, 53 mmole, 1.05 eq.) is addedrapidly. The cold bath is then removed and the mixture stirred for 1hour. The reaction is monitored by TLC to insure completion of thereaction and the mixture is then filtered and washed with dry THF (50ml) and kept cold in the filtered flask at −20 degrees C.

In an ice-salt bath is placed a 500 ml graduate cylinder containingether (200 mL) and aqueous potassium hydroxide (40%, 60 ml).1-Methyl-3-nitro-1-nitrosoguanidine (5.6 g, 106 mmole, 2.1 eq.) is addedslowly with stirring and temperature kept below 0 degrees C. The mixtureturned yellow and the bubbling lasted for 10 minutes. The stirring isstopped and without mixing the layers, the top diazomethane ethereallayer is transferred with non-ground tip pipette into the stirred mixedanhydride mixture at −20 degrees C. The reaction is monitored by TLC(ethyl acetate/hexane, 50/50; R_(f)=0.69). After 1 hour nitrogen is thenbubbled into the mixture. The solvent is removed under reduced pressure(with heat) and the mixture is partitioned between ether and water. Thephases are separated, the organic phase is washed with bicarbonate,saline, dried over anhydrous sodium sulfate and solvent removed underreduced pressure (with heat). The residue is dissolved in ether (100 mL)and hydrobromic acid (48%, 15 mL, 135 mmole, 2.7 eq,) is added at −20degrees C., the cold bath is removed and the mixture is stirred foranother 0.5 hours. The reaction is monitored by TLC (ethylacetate/hexane, 50/50; R_(f)=0.88). The mixture is partitioned betweenether and water, washed with bicarbonate, saline, dried over anhydroussodium sulfate and the solvent removed. The residue is recrystallizedfrom ethanol to give the title compound, TLC (ethyl acetate/hexane,50/50) R_(f)=0.88; MS (MH⁺)=379.3.

Example 2 tert-Butyl(1S,2S)-3-bromo-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (IV)

Sodium borohydride (1.32 g, 34.9 mmole, 1.1 eq.) is added to tert-Butyl(1S)-3-bromo-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III, EXAMPLE1, 12 g, 31.75 mmole) dissolved in absolute alcohol (500 mL) at −78degrees C. The reaction mixture is stirred for 0.5 hour and monitored byTLC (ethyl acetate/hexane, 20/80; R_(f)=0.2). The mixture is quenchedwith water (10 mL) and the solvent removed under reduced pressure withheat (not exceeding 30 degrees C.) to dryness. The solid is partitionedbetween dichloromethane and water, washed with saline, dried overanhydrous sodium sulfate. The solvent is removed under reduced pressureto give the title compound, TLC (ethyl acetate/hexane, 20/80) R_(f)=0.2;MS (MH⁺)=381.2.

Example 3 tert-Butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V)

tert-Butyl(1S,2S)-3-bromo-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (IV,EXAMPLE 2) is dissolved in absolute alcohol (150 mL) and ethyl acetate(100 mL) and potassium hydroxide (2.3 g, 34.9 mmole, 1.1 eq.) in ethylalcohol (85%, 5 mL) is added at −20 degrees C. The cold bath is thenremoved and the mixture stirred for 0.5 hour. The reaction is monitoredby TLC (ethyl acetate/hexane, 20/80). When the reaction is complete, itis diluted with dichloromethane and extracted, washed with water,saline, dried over anhydrous sodium sulfate and the solvent removedunder reduced pressure. The crude material is purified by flashchromatography on silica gel to give the title compound, TLC (ethylacetate/hexane, 20/80) R_(f)=0.3; MS (MH⁺)=300.4.

Example 4 tert-Butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate(VII)

tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate(V, EXAMPLE 3, 245 mg, 0.82 mmol) is suspended in isopropyl alcohol (6mL) and 3-methoxybenzylamine (160 microL, 1.22 mmol) is added withstirring at 20–25 degrees C. This mixture is heated to gentle reflux(bath temp 85 degrees C.) under nitrogen for 2 hours, whereupon theresulting mixture is concentrated under reduced pressure to give thetitle compound. The title compound is purified by flash chromatography(2–5% methanol/methylene chloride; gradient elution) to give purifiedtitle compound.

Example 5(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanoltrifluoroacetate (VIII)

tert-Butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate(VII, EXAMPLE 4, 258 mg, 0.59 mmol) is dissolved in methylene chloride(1 mL) at 20–25 degrees C., and trifluoroacetic acid (1 mL) is addedwith stirring under nitrogen. The reaction mixture is stirred at 20–25degrees C. for 1 hour, whereupon the reaction mixture is concentratedunder reduced pressure to give the title compound. The title compound isused in the next reaction without further purification.

Example 6N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanoltrifluoroacetate salt (VIII, EXAMPLE 5) is dissolved in anhydrous DMF (3mL) and cooled to 0 degrees C. Triethylamine (500 microliter, 3.6 mmol)and 5-methyl-N, N-dipropylisophthalamic acid (156 mg, 0.59 mmol) areadded with stirring. The mixture is warmed to 20–25 degrees C. brieflyto allow for complete dissolution of the carboxylic acid, beforerecooling to 0 degrees C. 1-Hydroxybenzotriazole (157 mg, 1.2 mmol) isadded with stirring, followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (229 mg, 1.2mmol). The resulting mixture is stirred at 0 degrees C. for 5 minutes,then warmed to 20–25 degrees C. for 15 hours. The reaction mixture isthen quenched with aqueous citric acid (10%), and the mixture extractedthree times with ethyl acetate. The combined organic extracts are washedwith saturated sodium bicarbonate, saline, dried over sodium sulfate,filtered and concentrated under reduced pressure to give the titlecompound in crude form. This material is purified by flashchromatography (2–10% methanol/methylene chloride gradient elution) togive purified title compound, MS (ES) MH⁺=582.3.

Examples 7–9

Following the general procedure of EXAMPLE 1 and making non criticalvariations but starting with the protecting group of Column A and usingthe acid of Column B, the protected compound (III) of Column C isobtained:

EXAMPLE Column A Column B Column C 7 BOC Hydrochlorictert-butyl(1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate 8CBZ Hydrobromicbenzyl(1S)-3-bromo-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate 9 CBZHydrochloricbenzyl(1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate

Examples 10–12

Following the general procedure of EXAMPLE 2 and making non criticalvariations but starting with the protected compound (III) of Column A,the alcohol (IV) of Column B is obtained:

EXAMPLE Column A Column B 10 7 Tert-butyl(1S,2S)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate 11 8Benzyl(1S, 2S)-3-bromo-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate12 9 Benzyl(1S,2S)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate

Example 13 Benzyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V)

Following the general procedure of EXAMPLE 3 and making non criticalvariations but starting with the alcohol (IV) of EXAMPLE 12, the titlecompound is obtained.

Examples 14–107

Following the general procedure of EXAMPLE 4 and making non-criticalvariations but reacting tert-butyl(1S,2S)-1-(2-oxiranyl)-2-phenylethylcarbamate (V, commerciallyavailable) with the C-terminal amine (VI) of Column A, the protectedalcohol (VII) of Column B is obtained.

Column A Column B EXA C-terminal amine (VI) Protected alcohol (VII) 14H₂N—CH₂CH₃ tert-butyl(1S,2R)-1-benzyl-3-(ethylamino)-2-hydroxypropylcarbamate 15 H₂N—CH₂-phenyltert-butyl(1S, 2R)-1-benzyl-3-(benzylamino)-2-hydroxypropylcarbamate 16H₂N—CH(CH₃)₂ tert-butyl(1S,2R)-1-benzyl-3-(isoproylamino)-2-hydroxypropylcarbamate 17H₂N—CH₂-phenyl-4-CH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(4-methylbenzyl)amino]propylcarbamate 18H₂N—(CH₂)₂-phenyl-4-OCH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[2-(4-methoxyphenyl)ethyl]amino}propylcarbamate19 H₂N—CH₂-phenyl-3-OCH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]proylcarbamate 20H₂N—CH(-phenyl)-CO—OC₂H₅ ethyl({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}amino)(phenyl)ace-tate 21 H₂N—(CH₂)₂phenyl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(2-phenylethyl)amino]propylcarbamate 22H₂N—CH(—CH₂OH)—CH(OH)-phenyl-4-NO₂ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitro-phenyl)ethyl]amino}propylcarbamate 23 H₂N—CH₂-phenyl-2-Cl tert-butyl(1S,2R)-1-benzyl-3-[(2-chlorobenzyl)amino]-2-hydroxypropylcarbamate 24H₂N—CH₂-phenyl-4-Cl tert-butyl(1S,2R)-1-benzyl-3-[(4-chlorobenzyl)amino]-2-hydroxypropylcarbamate 25H₂N—(CH₂)₂—O—(CH₂)₂—OH tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[2-(2-hydroxyethoxy)ethyl]amino}propylcarbamate26 H₂N-1-indanyl tert-butyl(1S,2R)-1-benzyl-3-(2,3-dihydro-1H-inden-1-ylamino)-2-hydroxypropylcarbamate27 H₂N—CH₂—CH(OH)—CH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(2-hydroxypropyl)amino]propylcarbamate 28H₂N—CH₂-tetrahydrofuranyl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(tetrahydro-2-furanylmethyl)amino]propylcarbamate29 H₂N—CH₂—CH(—OCH₂CH₃) tert-butyl(1S,2R)-1-benzyl-3-[(2,2-diethoxyethyl)amino]-2-hydroxypropylcarbamate 30H₂N—(CH₂)₄—CH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-(pentylamino)propylcarbamate 31 H₂N-cyclohexyltert-butyl(1S, 2R)-1-benzyl-3-(cyclohexylamino)-2-hydroxypropylcarbamate32 H₂N—CH₂-pyridin-2-yl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(2-pyridinylmethyl)amino]propylcarbamate 33H₂N—CH₂-phenyl-2-NH₂ tert-butyl(1S,2R)-3-[(2-aminobenzyl)amino]-1-benzyl-2-hydroxypropylcarbamate 34H₂N—CH₂-pyridin-3-yl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(3-pyridinylmethyl)amino]propylcarbamate 35H₂N—(CH₂)₂-pyrrolidin-1-yl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[2-(1-pyrrolidinyl)ethyl]amino}propylcarbamate36 H₂N—CH₂—CH(OH)-phenyl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(2-hydroxy-2-phenylethyl)amino]propylcarbamate37 H₂N—(CH₂)₃—O—(CH₂)₃—CH₃ tert-butyl(1S,2R)-1-benzyl-3-[(3-butoxypropyl)amino]-2-hydroxypropylcarbamate 38H₂N—(CH₂)₃—O—CH(CH₃)₂ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(3-isopropoxypropyl)amino]propylcarbamate 39H₂N—(CH₂)₂—CH(CH₃)₂ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-(isopentylamino)propylcarbamate 40H₂N—(CH₂)₃-phenyl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(3-phenylpropyl)amino]propylcarbamate 41H₂N—(CH₂)₂—OCH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(2-methoxyethyl)amino]propylcarbamate 42H₂N—(CH₂)₂—O-phenyl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(2-phenoxyethyl)amino]propylcarbamate 43H₂N—(CH₂)₂—O—(CH₂)₂—CH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(2-propoxyethyl)amino]propylcarbamate 44H₂N—(CH₂)₂—C(CH₃)₃ tert-butyl(1S,2R)-1-benzyl-3-[(3,3-dimethylbutyl)amino]-2-hydroxypropylcarbamate 45H₂N—(CH₂)₄-phenyl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(4-phentylbutyl)amino]propylcarbamate 46H₂N—CH₂-phenyl-3-I tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propylcarbamate 47H₂N—CH₂-phenyl-4-NO₂ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(4-nitrobenzyl)amino]propylcarbamate 48H₂N—CH₂-phenyl-3-Cl tert-butyl(1S,2R)-1-benzyl-3-[(3-chlorobenzyl)amino]-2-hydroxypropylcarbamate 49H₂N—(CH₂)₂-phenyl-4-Cl tert-butyl(1S,2R)-1-benzyl-3-{[2-(4-chlorophenyl)ethyl]amino}-2-hydroxypropylcarbamate50 H₂N—(CH₂)₂-pyridin-2-yl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[2-(2-pyridinyl)ethyl]amino}propylcarbamate 51H₂N—CH₂-pyridin-4-yl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(4-pyridinylmethyl)amino]propylcarbamate 52H₂N—(CH₂)₂—(N-methylpyrrolidin-2-yl) tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}propyl-carbamate 53 H₂N—CH₂-phenyl-2,3-dimethyl tert-butyl(1S,2R)-1-benzyl-3-[(2,3-dimethylbenzyl)amino]-2-hydroxypropylcarbamate 54H₂N—CH₂-phenyl-2-OCF₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[2-(trifluoromethoxy)benzyl]amino}propyl-carbamate 55 H₂N—CH₂-phenyl-2-Cl-6-O-phenyl tert-butyl(1S,2R)-1-benzyl-3-[(2-chloro-6-phenoxybenzyl)amino]-2-hydroxypropylcarbamate56 H₂N—CH₂-phenyl-4-CF₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[4-(trifluoromethyl)benzyl]amino}propylcarbamate57 H₂N—CH₂-phenyl-2,3-dichloro tert-butyl(1S,2R)-1-benzyl-3-[(2,3-dichlorobenzyl)amino]-2-hydroxypropylcarbamate 58H₂N—CH₂-phenyl-3,5-dichloro tert-butyl(1S,2R)-1-benzyl-3-[(3,5-dichlorobenzyl)amino]-2-hydroxypropylcarbamate 59H₂n—CH₂-phenyl-3,5-difluoro tert-butyl(1S,2R)-1-benzyl-3-[(3,5-difluorobenzyl)amino]-2-hydroxypropylcarbamate 60H₂N—CH₂-phenyl-4-OCF₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[4-(trifluoromethoxy)benzyl]amino}propyl-carbamate 61 H₂N—(CH₂)₂-phenyl-4-SO₂—NH₂ tert-butyl(1S,2R)-3-{[4-(aminosulfonyl)benzyl]amino}-1-benzyl-2-hydroxypropylcarbamate62 H₂N—CH₂-phenyl-4-OCH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(4-methoxybenzyl)amino]propylcarbamate 63H₂N—CH₂-phenyl-4-CH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(4-methylbenzyl)amino]propylcarbamate 64H₂N—CH₂—Ph-(3,4,5-trimethoxy) tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(3,4,5-trimethoxybenzyl)amino]propylcarbamate65 H₂N—CH₂-phenyl-3-OCF₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethoxy)benzyl]amino}propyl-carbamate 66 H₂—CH₂-phenyl-3,5-dimethoxy tert-butyl(1S,2R)-1-benzyl-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxypropylcarbamate 67H₂N—CH₂-phenyl-2,4-dimethoxy tert-butyl(1S,2R)-1-benzyl-3-[(2,4-dimethoxybenzyl)amino]-2-hydroxypropylcarbamate 68H₂N—CH₂-phenyl-phenyl tert-butyl(1S,2R)-1-benzyl-3-[([1,1′-biphenyl]-3-ylmethyl)amino]-2-hydroxypropylcarbamate69 H₂N—CH₂-phenyl-3,4-dichloro tert-butyl(1S,2R)-1-benzyl-3-[(3,4-dichlorobenzyl)amino]-2-hydroxypropycarbamate 70H₂N—CH₂-phenyl-4-F tert-butyl(1S,2R)-1-benzyl-3-[(4-fluorobenzyl)amino]-2-hydroxypropylcarbamate 71H₂N—CH₂-phenyl-3-CF₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propylcarbamate72 H₂N—CH₂-phenyl-2-CH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(2-methylbenzyl)amino]propylcarbamate 73H₂N—CH(R)—CH₃)-phenyl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-1-phenylethyl]amino}propylcarbamate 74H₂N—CH((S)—CH₃)-phenyl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-1-phenylethyl]amino}propylcarbamate 75H₂N—CH₂-phenyl-3,5-(bis)trifluoromethyl tert-butyl(1S,2R)-1-benzyl-3-{[3,5-bis(trifluoromethyl)benzyl]amino}-2-hydroxy-propylcarbamate 76 H₂N—CH₂-phenyl-2-CF₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[2-(trifluoromethyl)benzyl]amino}propylcarbamate77 H₂N—CH((S)—CH₃)-(naphth-1-yl) tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-1-(1-naphthyl)ethyl]amino}propylcarbamate78 —NH₂—CH(R)—CH₃)-(naphth-1-yl) tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-1-(1-naphthyl)ethyl]amino}propylcarbamate79 H₂N—CH₂-phenyl-3-OCH₃-4-OH tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(4-hydroxy-3-methoxybenzyl)amino]propyl-carbamate 80 H₂N—CH₂-phenyl-3,4-dihydroxy tert-butyl(1S,2R)-1-benzyl-3-[(3,4-dihydroxybenzyl)amino]-2-hydroxypropylcarbamate 81H₂N—(CH₂)₃—OCH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxypropyl)amino]propylcarbamate 82H₂N—CH((S)—CH₃)—CH₂—OH tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-2-hydroxy-1-methylethyl]amino}propyl-carbamate 83 H₂N—CH((R)—CH₃)—CH₂—OH tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-2-hydroxy-1-methylethyl]amino}propyl-carbamate 84 H₂N—CH₂—C≡CH tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-(2-propynylamino)propylcarbamate 85H₂N—(CH₂)₂-phenyl-2-F tert-butyl(1S,2R)-1-benzyl-3-{[2-(2-fluorophenyl)ethyl]amino}-2-hydroxypropylcarbamate86 H₂N—(CH₂)₂-phenyl-3-F tert-butyl(1S,2R)-1-benzyl-3-{[2-(3-fluorophenyl)ethyl]amino}-2-hydroxypropylcarbamate87 H₂N—(CH₂)₂-phenyl-4-F tert-butyl(1S,2R)-1-benzyl-3-{[2-(4-fluorophenyl)ethyl]amino}-2-hydroxypropylcarbamate88 H₂N—(CH₂)₂-phenyl-4-Br tert-butyl(1S,2R)-1-benzyl-3-{[2-(4-bromophenyl)ethyl]amino}-2-hydroxypropylcarbamate89 H₂N—(CH₂)₂-phenyl-3-OCH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[2-(3-methoxyphenyl)ethyl]amino}propylcarbamate90 H₂N—(CH₂)₂-phenyl-2,4-dichloro tert-butyl(1S,2R)-1-benzyl-3-{[2-(2,4-dichlorophenyl)ethyl]amino}-2-hydroxy-propylcarbamate 91 H₂N—(CH₂)₂-phenyl-3-Cl tert-butyl(1S,2R)-1-benzyl-3-{[2-(3-chlorophenyl)ethyl]amino}-2-hydroxypropylcarbamate92 H₂N—(CH₂)₂-phenyl-2,5-dimethoxy tert-butyl(1S,2R)-1-benzyl-3-{[2-(2,5-dimethoxyphenyl)ethyl]amino}-2-hydroxy-propylcarbamate 93 H₂N—(CH₂)₂-phenyl-4-CH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[2-(4-methylphenyl)ethyl]amino}propylcarbamate94 H₂N—CH(—(R)CH₂—OH)—CH₂-phenyl tert-butyl(1S,2R)-1-benzyl-3-{[(1R)-1-benzyl-2-hydroxyethyl]amino}-2-hydroxy-propylcarbamate 95 H₂N—(CH₂)₃-(1-morpholinyl) tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(4-morpholinyl)propyl]amino}propylcarbamate96 H₂N—CH₂—C(CH₃)₂ tert-butyl(1S,2R)-1-benzyl-3-[(3,3-dimethylbutyl)amino]-2-hydroxypropylcarbamate 97H₂N—(CH₂)₂-(1-morpholinyl) tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[2-(4-morpholinyl)ethyl]amino}propylcarbamate98 H₂N—CH(OH)—CH₂—CH₃ tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(1-hydroxypropyl)amino]propylcarbamate 99H₂N—(CH₂)₂-(thien-2-yl) tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(2-thienylmethyl)amino]propylcarbamate 100H₂N—(CH₂)₄—OH tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(4-hydroxybutyl)amino]propylcarbamate 101H₂N—CH(—(S)CH₂—OH)-phenyl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-2-hydroxy-1-phenylethyl]amino}propyl-carbamate 102 H₂N—CH₂-phenyl-2,4-dichloro tert-butyl(1S,2R)-1-benzyl-3-[(2,4-dichlorobenzyl)amino]-2-hydroxypropylcarbamate 103H₂N—CH(—(R)CH₂—OH)-phenyl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-2-hydroxy-1-phenylethyl]amino}propyl-carbamate 104 H₂N—CH₂-phenyl-4-C(CH₃)₃ tert-butyl(1S,2R)-1-benzyl-3-[(4-tert-butylbenzyl)amino]-2-hydroxypropylcarbamate 105H₂N—CH(CH₃)-phenyl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-[(1-phenylethyl)amino]propylcarbamate 106H₂N-(1R, 2S)-2-hydroxyinden-1-yl tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]a- mino}propylcarbamate 107H₂N—CH₂-phenyl-3,4-dimethyl tert-butyl(1S,2R)-1-benzyl-3-[(3,4-dimethylbenzyl)amino]-2-hydroxypropylcarbamate

Examples 108–164

Following the general procedure of EXAMPLE 4 and making non-criticalvariations but reacting tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3) with the C-terminal amine (VI) of Column A, the protected alcohol(VII) of Column B is obtained.

Column A Column B EXA C-terminal amin (VI) Protected alcohol (VII) 108H₂N—(CH₂)₆—CO—O—CH₃ methyl 7-{[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-4-(3,5-difluoro-phenyl)-2-hydroxybutyl]amino}heptanoate 109H₂N—CH(—CH₃)—CO—NH—CH₂—CH(CH₃)₂ r/s tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutyl-amino)-1-methyl-2-oxoethyl]amino}propylcarbamate 110H₂N—CH((S)—CH₃)—CO—NH—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(iso-butylamino)-1-methyl-2-oxoethyl]amino}propylcarbamate 111H₂N—C(—CH₃)₂—CO—NH—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutyl-amino)-1,1-dimethyl-2-oxoethyl]amino}propylcarbamate 112H₂N—CH₂—CO—NH—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutyl-amino)-2-oxoethyl]amino}propylcarbamate 113H₂N—CH((S)—CH₂CH₃)—CO—NH—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(iso-butylamino)carbonyl]propyl}amino)propylcarbamate 114H₂N—CH((R)—CH₂CH₃)—CO—NH—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1R)-1-[(iso-butylamino)carbonyl]propyl}amino)propylcarbamate 115 H₂N—CH₂-phenyltert-butyl(1S, 2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxy-propylcarbamate 116 H₂N—CH₂—CH₃ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-3-(ethyl- amino)-2-ydroxypropylcarbamate 117H₂N—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isobutyl- amino)propylcarbamate118 H₂N—CH₂—CH(CH₃)—CONH—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(isobutyl-amino)-2-methyl-3-oxopropyl]amino}propylcarbamate 119H₂N—CH₂-phenyl-4-N(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-3-{[4-(dimethyl-amino)benzyl]amino}-2-hydroxypropylcarbamate 120H₂N—CH((S)—CH₂-phenyl)-CO—NH—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-3-{[(1S)-1-(3,5-difluorobenzyl)-2-(isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate 121H₂N—CH((S)—CH(CH₃)₂)—CO—NH—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(iso-butylamino)carbonyl]-3-methylbutyl}amino)propylcarbamate 122H₂N—CH₂—CH₂—N(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-3-{[2-(dimethyl-amino)ethyl]amino}-2-hydroxypropylcarbamate 123 H₂N—CH₂-(pyridin-3-yl)tert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-pyridinyl-methyl)amino]propylcarbamate 124H₂N—CH((S)—CH₂—O—CH₂-phenyl)-CO—NH—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-3-{[(1S)-1-[(benzyloxy)methyl]-2-(isobutyl-amino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hdyroxy-propylcarbamate 125 H₂N—C(—CH₃)₂-phenyl tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-meth-yl-1-phenylethyl)amino]propylcarbamate 126H₂N—CH((R)—CH(CH₃)₂)—CO—NH—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1R)-1-[(iso-butylamino)carbonyl]-3-methylbutyl}amino)propylcarbamate 127H₂N—CH((S)—CH₂—CH₂—CH₃)—CO—NH—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(iso-butylamino)carbonyl]butyl}amino)propylcarbamate 128H₂N—CH((S)—CH₂—OH)—CO—NH—CH₂—CH(CH₃)₂ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-1-(hy-droxymethyl)-2-(isobutylamino)-2-oxoethyl]amino}propylcarbamate 129H₂N—CH₂—CH₂-phenyl tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenyl-ethyl)amino]propylcarbamate 130 H₂N—CH((S)—CH₃)—CO—NH—CH₂-phenyltert-butyl(1S, 2R)-3-{[2-(benzylamino)-1-methyl-2-ox-oethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate 131H₂N—CH((S)—CH₂—CH₃)-phenyl tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-2-(benzyl-amino)-1-methyl-2-oxoethyl]amino}-2-hydroxypropylcarbamate 132H₂N—CH₂-phenyl-3-OCH₃ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxy-benzyl)amino]propylcarbamate 133 H₂N—CH((S)-phenyl)CO—NHCH₂CH(CH₃)₂tert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(iso-butylamino)-2-oxo-1-phenylethyl]amino}propylcarbamate 134H₂N—CH₂—CH₂—CH(CH₃)₂ tert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-2-hy-droxy-3-(isopentylamino)propylcarbamate 135 H₂N-cyclohexyltert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-3-(cyclohexylamino)-2-hy-droxypropylcarbamate 136 H₂N—(CH₂)₃—CH₃ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-3-(butylamino)-2-hydroxy- propylcarbamate 137H₂N—(CH₂)₃-O—CH₃ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxy-propyl)amino]propylcarbamate 138 H₂N—CH₂—CH(OH)-phenyl tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-hy-droxy-2-phenylethyl)amino]propylcarbamate 139H₂N-cyclohexyl-3,5-dimethoxy tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3R, 5S)-3,5-dimethoxy-cyclohexyl]amino}-2-hydroxypropylcarbamate 140H₂N-cyclohexyl-3,5-di-(—CO—OCH₃) dimethyl(1R, 3S)-5-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hy-droxy-4-phenylbutyl}amino)-1,3-cyclohexanedicarboxylate 141H₂N-cyclohexyl-3,5-di-(—COOH) (1R, 3S)-5-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hy-droxy-4-phenylbutyl}amino)-1,3-cyclohexanedicarboxylic acid 142H₂N—CH(R)—CH₂—CH₃)-phenyl tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R)-1-phenyl-propyl]amino}propylcarbamate 143 H₂N—CH₂-phenyl-3-Cl tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-chloro-benzyl)amino]-2-hydroxypropylcarbamate 144 H₂N—CH₂-phenyl-3-OCH₃tert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxy-benzyl)amino]propylcarbamate 145 H₂N—CH₂-phenyl-phenyl tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-3-[((1,1′-biphenyl]-3-ylmeth-yl)amino]-2-hydroxypropylcarbamate 146 H₂N—CH₂-phenyl-3-I tert-butyl(1S,2R)-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodo-benzyl)amino]propylcarbamate 147 H₂N—CH₂-phenyl-3-CH₃ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methyl-benzyl)amino]propylcarbamate 148 H₂N—CH₂—CH(—CH₃)-phenyl tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenyl-propyl)amino]propylcarbamate 149 H₂N—CH₂-(thiazol-5-yl) tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1,3-thia-zol-5-ylmethyl)amino]propylcarbamate 150 H₂N—CH₂-(thien-2-yl)tert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-thienyl-methyl)amino]propylcarbamate 151 H₂N-4-methoxytetralin-1-yltert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-meth-oxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propylcarbamate 152H₂N—CH₂-pyrazin-2-yl tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-pyrazinyl-methyl)amino]propylcarbamate 153 H₂N—CH₂-phenyl-3,5-difluorotert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-3-[(3,5-difluoro-benzyl)amino]-2-hydroxypropylcarbamate 154H₂N—CH₂-phenyl-3,4-methylenedioxy tert-butyl(1S,2R)-3-[(1,3-benzodioxol-5-ylmethyl)amino]-1-(3,5-di-fluorobenzyl)-2-hydroxypropylcarbamate 155 H₂N—CH₂-phenyl-3,5-dimethoxytert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-3-[(3,5-dimethoxy-benzyl)amino]-2-hydroxypropylcarbamate 156 H₂N—CH₂-phenyl-3-CF₃tert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoro-methyl)benzyl]amino}propylcarbamate 157 H₂N—CH₂-(furan-2-yl)tert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-3-[(2-furylmethyl)a-mino]-2-hydroxypropylcarbamate 158 H₂N-(7-methoxytetralin-1-yl)tert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-meth-oxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propylcarbamate 159H₂N—CH₂-phenyl-3-O—CF₃ tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoro-methoxy)benzyl]amino}propylcarbamate 160 H₂N—CH₂-phenyl-3-Ftert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-3-[(3-fluoro-benzyl)amino]-2-hydroxypropylcarbamate 161 H₂N—CH₂-phenyl-3-O—CH(CH₃)₂tert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iso-propoxybenzyl)amino]propylcarbamate 162 H₂N—CH₂-phenyl-3-Brtert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-3-[(3-bromo-benzyl)amino]-2-hydroxypropylcarbamate 163 H₂N—CH₂-(5-methylfuran-2-yl)tert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-meth-yl-2-furyl)methyl]amino}propylcarbamate 164 H₂N-(5-methoxytetralin-1-yl)tert-butyl(1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-meth-oxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propylcarbamate

Example 165tert-Butyl-(1S,2R)-3-azido-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate(XII)

Sodium azide (0.22 g, 4 mmole) and ammonium chloride (2 eq) are added totert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate(V, EXAMPLE 3, 0.6 g, 2 mmole). The reaction is heated to 75–80 degreesC. and stirred for 16 hours. The reaction is monitored by TLC to insurecompletion. The solvent is removed under reduced pressure. Theconcentrate is partitioned between ethyl acetate and water, the phasesare separated and the organic phase is washed with bicarbonate andsaline, dried over anhydrous sodium sulfate and concentrated to give thetitle compound, TLC (ethyl acetate/hexane) R_(f)=0.45; MS (MH⁺)=343.

Example 166 (2R,3S)-3-amino-1-azido-4-(3,5-difluorophenyl)-2-butanol(XIV)

tert-Butyl-(1S,2R)-3-azido-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate(XII, EXAMPLE 165, 0.48 g, 1.41 mmole) is dissolved in dichloromethane(20 ml) to which trifluoroacetic acid (5 ml) is added. The reaction isstirred at 20–25 degrees C. for 16 hours and the solvent is removedunder reduced pressure with heat. Ethyl acetate is added twice andevaporated twice to give the title compound as the trifluoroacetic acidsalt which is used in the next reaction without further purification; MS(MH⁺)=242.

Example 167N¹-[(1S,2R)-3-azido-1-(3,5-difluorobenzyl)-2-hydroxypropyl]5-methyl-N³,N³-dipropylisophthalamide(XV)

To (2R,3S)-3-amino-1-azido-4-(3,5-difluorophenyl)-2-buta (XIV, EXAMPLE166, 0.34 g, 1.4 mmole) in dichloromethane (20 ml) is addedN,N-dipropylamidoisophthalic acid (IX, 0.53 g, 2 mmole), t-butyl alcohol(0.27 g, 2 mmole) and triethylamine (0.84 ml, 6 mmole) andethyl-1-(3-dimethylaminopropyl)carbodiimide (0.58 g, 3 mmole). Themixture is stirred at 20–25 degrees C. for 16 hours. The reaction ismonitored by TLC (methanol/dichloromethane, 20/80+ethyl acetate/hexane,50/50; R_(f)=0.76). When the reaction is complete as measured by TLC,the reaction mixture is partitioned between dichloromethane and water,washed with hydrochloric acid (0.5 N), bicarbonate, saline, dried overanhydrous sodium sulfate and the solvent is removed under reducedpressure with heat to produce a concentrate. The concentrate is columnchouromatographed on silica gel to give the title compound; MS(MH⁺)=488.

Example 168N¹-[(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamideacetic acid salt (XVI)

N¹-[(1S,2R)-3-azido-1-(3,5-difluorobenzyl)-2-hydroxypropyl]5-methyl-N³,N³-dipropylisophthalamide(XV, EXAMPLE 167, 0.3 g, 0.62 mmole) in ethyl acetate (20 ml) and aceticacid (5 ml) is placed in a Parr pressure bottle. Palladium on carbon(10%, 5 g) is added and the mixture shaken under hydrogen at 50 psi for2 hours. The mixture is filtered through a diatomaceous earth and thefiltrate is concentrated to give the title compound; MS (MH⁺)=462.

Example 169N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-furylmethyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

N¹-[(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamideacetic acid salt (XVI, EXAMPLE 168, 76 mg, 0.146 mmol) is dissolved inabsolute ethanol (2 mL). 3-Furaldehyde (20 microL, 0.231 mmol) andtriethylamine (30 microL, 0.215 mmol) are added via syringe, withstirring at 20–25 degrees C. After 10 minutes, palladium on carbon 122mg, 5 weight %) is added and the mixture placed under a hydrogenatmosphere (50 psi) and shaken for 20 minutes. The resulting mixture isthen filtered through diatomaceous earth, with ethanol washings. Thefiltrate is purified by flash chromatography (2–10% methanol/methylenechloride) to give purified title compound, MS (MH⁺)=542.2.

Example 169a tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-2-(ethylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxypropylcarbamate(VII)

Following the general procedure of EXAMPLEs 4 and 14–164 and makingnon-critical variations and reacting tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3) with (2S)-2-amino-N-ethylpropanamide (VI), the title compound isobtained.

Examples 170–320

Following the general procedure of EXAMPLE 5 and making non-criticalvariations but starting with the protected alcohol (VII) of Column A,the amine (VIII) of Column B is obtained.

Column A Protected Alcohol (VII) Compound of Column B EXA EXAMPLE Amine(VIII) 170 14 (2R, 3S)-3-amino-1-(ethylamino)-4-phenyl-2-butanol 171 15(2R, 3S)-3-amino-1-(benzylamino)-4-phenyl-2-butanol 172 16 (2R,3S)-3-amino-1-(isopropylamino)-4-phenyl-2-butanol 173 17 (2R,3S)-3-amino-1-[(4-methylbenzyl)amino]-4-phenyl-2-butanol 174 18 (2R,3S)-3-amino-1-{[2-(4-methoxyphenyl)ethyl]amino}-4-phenyl-2-butanol 17519 (2R, 3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanol 176 20ethyl{[(2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl]amino}(phenyl)acetate177 21 (2R, 3S)-3-amino-4-phenyl-1-[(2-phenylethyl)amino]-2-butanol 17822 (2S)-2-{[2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]amino}-1-(4-nitorphenyl)-1,3-propanediol179 23 (2R, 3S)-3-amino-1-[(2-chlorobenzyl)amino]-4-phenyl-2-butanol 18024 (2R, 3S)-3-amino-1-[(4-chlorobenzyl)amino]-4-phenyl-2-butanol 181 25(2R, 3S)-3-amino-1-{[2-(2-hydroxyethoxy)ethyl]amino}-4-phenyl-2-butanol182 26 (2R,3S)-3-amino-1-(2,3-dihydro-1H-inden-1-ylamino)-4-phenyl-2-butanol 183 27(2R, 3S)-3-amino-1-[(2-hydroxypropyl)amino]-4-phenyl-2-butanol 184 28(2R, 3S)-3-amino-4-phenyl-1-[(tetrahydr-2-furanylmethyl)amino]-2-butanol185 29 (2R, 3S)-3-amino-1-[(2,2-diethoxyethyl)amino]-4-phenyl-2-butanol186 30 (2R, 3S)-3-amino-1-(butylamino)-4-phenyl-2-butanol 187 31 (2R,3S)-3-amino-1-(cyclohexylamino-4-phenyl-2-butanol 188 32 (2R,3S)-3-amino-4-phenyl-1-[2-pyridinylmethyl)amino]-2-butanol 189 33 (2R,3S)-3-amino-1-[(2-aminobenzyl)amino]-4-phenyl-2-butanol 190 34 (2R,3S)-3-amino-4-phenyl-1-[(3-pyridinylmethyl)amino]-2-butanol 191 35 (2R,3S)-3-amino-4-phenyl-1-{[2-(1-pyrrolidinyl)ethyl]amino}-2-butanol 192 36(2R, 3S)-3-amino-1-[(2-hydroxy-2-phenylethyl)amino]-4-phenyl-2-butanol193 37 (2R, 3S)-3-amino-1-[(3-butoxypropyl)amino]-4-phenyl-2-butanol 19438 (2R, 3S)-3-amino-1-[(3-isopropoxypropyl)amino]-4-phenyl-2-butanol 19539 (2R, 3S)-3-amino-1-(isopentylamino)-4-phenyl-2-butanol 196 40 (2R,3S)-3-amino-4-phenyl-1-[(3-phenylpropyl)amino]-2-butanol 197 41 (2R,3S)-3-amino-1-[(2-methoxyethyl)amino]-4-phenyl-2-butanol 198 42 (2R,3S)-3-amino-1-[(2-phenoxyethyl)amino]-4-phenyl-2-butanol 199 43 (2R,3S)-3-amino-4-phenyl-1-[(2-propoxyethyl)amino]-2-butanol 200 44 (2R,3S)-3-amino-1-[(3,3-dimethylbutyl)amino]-4-phenyl-2-butanol 201 45 (2R,3S)-3-amino-4-phenyl-1-[(4-phenylbutyl)amino]-2-butanol 202 46 (2R,3S)-3-amino-1-[(3-iodobenzyl)amino]-4-phenyl-2-butanol 203 47 (2R,3S)-3-amino-1-[(4-nitrobenzyl)amino]-4-phenyl-2-butanol 204 48 (2R,3S)-3-amino-1-[(3-chlorobenzyl)amino]-4-phenyl-2-butanol 205 49 (2R,3S)-3-amino-1-{[2-(4-chlorophenyl)ethyl]amino}-4-phenyl-2-butanol 206 50(2R, 3S)-3-amino-4-phenyl-1-{[2-(2-pyridinyl)ethyl]amino}-2-butanol 20751 (2R, 3S)-3-amino-4-phenyl-1-[(4-pyidinylmethyl)amino]-2-butanol 20852 (2R,3S)-3-amino-1-{[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}-4-phenyl-2-butanol209 53 (2R, 3S)-3-amino-1-[(2,3-dimethylbenzyl)amino]-4-phenyl-2-butanol210 54 (2R,3S)-3-amino-4-phenyl-1-{[2-(trifluoromethoxy)benzyl]amino}-2-butanol 21155 (2R,3S)-3-amino-1-[(2-chloro-6-phenoxybenzyl)amino]-4-phenyl-2-butanol 21256 (2R,3S)-3-amino-4-phenyl-1-{[4-(trifluoromethyl)benzyl]amino}-2-butanol 21357 (2R, 3S)-3-amino-1-[(2,3-dichlorobenzyl)amino]-4-phenyl-2-butanol 21458 (2R, 3S)-3-amino-1-[(3,5-dichlorobenzyl)amino]-4-phenyl-2-butanol 21559 (2R, 3S)-3-amino-1-[(3,5-difluorobenzyl)amino]-4-phenyl-2-butanol 21660 (2R,3S)-3-amino-4-phenyl-1-{[4-(trifluoromethoxy)benzyl]amino}-2-butanol 21761 4-({[2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]amino}methyl)benzenesulfonamide 21862 (2R, 3S)-3-amino-1-[(4-methoxybenzyl)amino]-4-phenyl-2-butanol 219 63(2R, 3S)-3-amino-1-[(4-methylbenzyl)amino]-4-phenyl-2-butanol 220 64(2R, 3S)-3-amino-4-phenyl-1-[(3,4,5-trimethoxybenzyl)amino]-2-butanol221 65 (2R,3S)-3-amino-4-phenyl-1-{[3-(trifluoromethoxy)benzyl]amino}-2-butanol 22266 (2R, 3S)-3-amino-1-[3,5-dimethoxybenzyl)amino]-4-phenyl-2-butanol 22367 (2R, 3S)-3-amino-1-[(2,4-dimethoxybenzyl)amino]-4-phenyl-2-butanol224 68 (2R,3S)-3-amino-1-[([1,1′-biphenyl]-3-ylmethyl)amino]-4-phenyl-2-butanol 22569 (2R, 3S)-3-amino-1-[(3,4-dichlorobenzyl)amino]-4-phenyl-2-butanol 22670 (2R, 3S)-3-amino-1-[(2-fluorobenzyl)amino]-4-phenyl-2-butanol 227 71(2R, 3S)-3-amino-4-phenyl-1-{[3-(trifluoromethyl)benzyl]amino}-2-butanol228 72 (2R, 3S)-3-amino-1-[(2-methylbenzyl)amino]-4-phenyl-2-butanol 22973 (2R, 3S)-3-amino-4-phenyl-1-{[(1R)-1-phenylethyl]amino}-2-butanol 23074 (2R, 3S)-3-amino-4-phenyl-1-{[(1S)-1-phenylethyl]amino}-2-butanol 23175 (2R,3S)-3-amino-1-{[3,5-bis(trifluoromethyl)benzyl]amino}-4-phenyl-2-butanol232 76 (2R,3S)-3-amino-4-phenyl-1-{[2-(trifluoromethyl)benzyl]amino}-2-butanol 23377 (2R,3S)-3-amino-1-{[(1S)-1-(1-naphthyl)ethyl]amino}-4-phenyl-2-butanol 23478 (2R,3S)-3-amino-1-{[(1R)-1-(1-naphthyl)ethyl]amino}-4-phenyl-2-butanol 23579 4-({[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]amino}methyl)-2-methoxyphenol 236 804-({[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]amino}methyl)-1,2-benzenediol 237 81(2R, 3S)-3-amino-1-[(3-methoxypropyl)amino]-4-phenyl-2-butanol 238 82(2R,3S)-3-amino-1-{[(1S)-2-hydroxy-1-methylethyl]amino}-4-phenyl-2-butanol239 83 (2R,3S)-3-amino-1-{[(1R)-2-hydroxy-1-methylethyl]amino}-4-phenyl-2-butanol240 84 (2R, 3S)-3-amino-4-phenyl-1-(2-propynylamino)-2-butanol 241 85(2R, 3S)-3-amino-1-{[2-(2-fluorophenyl)ethyl]amino}-4-phenyl-2-butanol242 86 (2R,3S)-3-amino-1-{[2-(3-fluorophenyl)ethyl]amino}-4-phenyl-2-butanol 243 87(2R, 3S)-3-amino-1-{[2-(4-fluorophenyl)ethyl]amino}-4-phenyl-2-butanol244 88 (2R,3S)-3-amino-1-{[2-(4-bromophenyl)ethyl]amino}-4-phenyl-2-butanol 245 89(2R, 3S)-3-amino-1-{[2-(3-methoxyphenyl)ethyl]amino}-4-phenyl-2-butanol246 90 (2R,3S)-3-amino-1-{[2-(2,4-dichlorophenyl)ethyl]amino}-4-phenyl-2-butanol247 91 (2R,3S)-3-amino-1-{[2-(3-chlorophenyl)ethyl]amino}-4-phenyl-2-butanol 248 92(2R,3S)-3-amino-1-{[2-(2,5-dimethoxyphenyl)ethyl]amino}-4-phenyl-2-butanol249 93 (2R,3S)-3-amino-1-{[2-(4-methylphenyl)ethyl]amino}-4-phenyl-2-butanol 250 94(2R,3S)-3-amino-1-{[(1R)-1-benzyl-2-hydroxyethyl]amino}-4-phenyl-2-butanol251 95 (2R,3S)-3-amino-1-{[3-(4-morpholinyl)propyl]amino}-4-phenyl-2-butanol 252 96(2R, 3S)-3-amino-1-(isobutylamino)-4-phenyl-2-butanol 253 97 (2R,3S)-3-amino-1-{[2-(4-morpholinyl)ethyl]amino}-4-phenyl-2-butanol 254 98(2R, 3S)-3-amino-4-phenyl-1-[(2-hydroxybutyl)amino]-2-butanol 255 99(2R, 3S)-3-amino-4-phenyl-1-{[2-(2-thienyl)ethyl]amino}-2-butanol 256100 4-{[(2R, 3S)-3-amino-2-hydroxy-4-phenylbutyl]amino}-1-butanol 257101 (2R,3S)-3-amino-1-{[(1S)-2-hydroxy-1-phenylethyl]amino}-4-phenyl-2-butanol258 102 (2R,3S)-3-amino-1-[(2,4-dichlorobenzyl)amino]-4-phenyl-2-butanol 259 103(2R,3S)-3-amino-1-{[(1R)-2-hydroxy-1-phenylethyl]amino}-4-phenyl-2-butanol260 104 (2R,3S)-3-amino-1-[(4-tert-butylbenzyl)amino]-4-phenyl-2-butanol 261 105(2R, 3S)-3-amino-4-phenyl-1-[(1-phenylethyl)amino]-2-butanol 262 106(1R, 2S)-1-{[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]amino}-2,3-dihydro-1H-inden-2-ol 263107 (2R, 3S)-3-amino-1-[(3,4-dimethylbenzyl)amino]-4-phenyl-2-butanol264 108 methyl 7-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}heptanoate 265109 2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-isobutylpropanamide266 110 (2S)-2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-isobutylpropanamide267 111 2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-isobutyl-2-methylpropanamide268 112 2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-isobutylacetamide269 113 (2S)-2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-isobutylbutanamide270 114 (2R)-2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-isobutylbutanamide271 115 (2R,3S)-3-amino-1-(benzylamino)-4-(3,5-difluorophenyl)-2-butanol 272 116(2R, 3S)-3-amino-4-(3,5-difluorophenyl)-1-(ethylamino)-2-butanol 273 117(2R, 3S)-3-amino-4-(3,5-difluorophenyl)-1-(isobutylamino)-2-butanol 274118 3-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-isobutyl-2-methylpropanamide275 119 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[4-(dimethylamino)benzyl]amino}-2-butanol276 120 (2S)-2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-isobutyl-3-phenylpropanamide277 121 (2S)-2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-isobutyl-3-methylbutanamide278 122 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[2-(dimethylamino)ethyl]amino}-2-butanol279 123 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-pyridinylmethyl)amino]-2-butanol280 124 (2S)-2-{[(2S,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-3-(benzyloxy)-N-isobutylpropanamide281 125 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(1-methyl-1-phenylethyl)amino]-2-butanol282 126 (2R)-2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-isobutyl-3-methylbutanamide283 127 (2S)-2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-isobutylpentanamide284 128 (2S)-2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-3-hydroxy-N-isobutylpropanamide285 129 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(2-phenylethyl)amino]-2-butanol286 130 (2S)-2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-benzylpropanamide287 131 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[(1S)-1-phenylpropyl]amino}-2-butanol 287a 169a  (2S)-2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-ethylpropanamide288 132 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol289 133 (2S)-2-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-N-isobutyl-2-phenylethanamide290 134 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-(isopentylamino)-2-butanol 291 135(2R, 3S)-3-amino-1-(cyclohexylamino)-4-(3,5-difluorophenyl)-2-butanol292 136 (2R, 3S)-3-amino-1-(butylamino)-4-(3,5-difluorophenyl)-2-butanol293 137 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxypropyl)amino]-2-butanol294 138 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(2-hydroxy-2-phenylethyl)amino]-2-butanol295 139 (2R, 3S)-3-amino-4-(3,5-difluorophenyl)-1-{[(3R,5S)-3,5-dimethoxycyclohexyl]amino}-2-butanol 296 140 dimethyl(1R,3S)-5-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-1,3-cyclohexanedicarboxylate297 141 (1R, 3S)-5-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-1,3-cyclohexanedicarboxylicacid 298 142 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[(1R)-1-phenylpropyl]amino}-2-butanol299 143 (2R,3S)-3-amino-1-[(3-chlorobenzyl)amino]-4-(3,5-difluorophenyl)-2-butanol300 144 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol301 145 (2R,3S)-3-amino-1-[([1,1′-biphenyl]-3-ylmethyl)amino]-4-(3,5-difluorophenyl)-2-butanol302 146 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-iodobenzyl)amino]-2-butanol 303147 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methylbenzyl)amino]-2-butanol304 148 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(2-phenylpropyl)amino]-2-butanol305 149 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(1,3-thiazol-5-ylmethyl)amino]-2-butanol306 150 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(2-thienylmethyl)amino]-2-butanol307 151 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]-2-butanol308 152 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(2-pyrazinylmethyl)amino]-2-butanol309 153 (2R,3S)-3-amino-1-[(3,5-difluorobenzyl)amino]-4-(3,5-difluorophenyl)-2-butanol310 154 (2R,3S)-3-amino-1-[(1,3-benzodioxol-5-ylmethyl)amino]-4-(3,5-difluorophenyl)-2-butanol311 155 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3,5-dimethoxybenzyl)amino]-2-butanol312 156 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[3-(trifluoromethyl)benzyl]amino}-2-butanol313 157 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(2-furylmethyl)amino]-2-butanol314 158 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(7-methoxy-1,2,3,4-tetrahydr-1-naphthalenyl)amino]-2-butanol315 159 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[3-(trifluoromethoxy)benzyl]amino}-2-butanol316 160 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-fluorobenzyl)amino]-2-butanol317 161 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-isopropoxybenzyl)amino]-2-butanol318 162 (2R,3S)-3-amino-1-[(3-bromobenzyl)amino]-4-(3,5-difluorophenyl)-2-butanol319 163 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(5-methyl-2-furylmethyl)amino]-2-butanol320 164 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]-2-butanol

Examples 321–473

Following the general procedure of EXAMPLE 6 and making non-criticalvariations but starting with the amine (VIII) of Column A and reactingit with the amide forming agent (IX) of Column B, the substituted amine(X) of Column C is obtained.

Column A Amine (VIII) Column B Column D Compound Amide Forming Column CPhysical EXA of EXA Agent (IX) Substitued amine (X) Data 321 170 “PHTH”N¹-[(1S,2R)-1-benzyl-3-(ethylamino)- MH⁺= 2-hydroxypropyl]-N³,N-³- 440.7dipropylisophthalamide 322 171 “PHTH” N¹-[(1S,2R)-1-benzyl-3- MH + =(benzylamino)-2-hydroxypropyl]- 502.7 N³,N³-dipropylisophthalamide 323172 “PHTH” N¹-[(1S,2R)-1-benzyl-2-hydroxy-3- MH + =(isopropylamino)propyl]-N³,N³- 454.6 dipropylisophthalamide 324 173“PHTH” N¹-[(1S,2R)-1-benzyl-2-hydroxy-3- MH + =(4-toluidino)propyl]-N³,N³- 502.2 dipropylisophthalamide 325 174 “P11TH”N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + ={[2-(4-methoxyphenyl)ethyl]amino} 546propyl)-N³,N³-ipropylisophthalamide 326 175 “PHTH”N^(-{(1S,2R)-1-benzyl-2-hydroxy-3-) MH + =[(3-methoxybenzyl)amino]propyl}- 532 N³,N³-dipropylisophthalamide 327176 “PHTH” ethyl {[(3S)-3-({3-[(dipropylamino) MH + = carbonyl]benzoyl}amino)-2-hydroxy- 574 4-phenylbutyl]amino}(phenyl)acetate 329178 “PHTH” N¹-((1S)-1-benzyl-2-hydroxy-3- MH + ={[(1S)-2-hydroxy-1-(hydroxymethyl)- 6072-(4-nitrophenyl)ethyl]amino}propyl) -N³,N³-dipropylisophthalamide 330179 “PHTH” N¹-{(1S,2R)-1-benzyl-3-[(2- MH + = chlorobenzyl)amino]-2- 537hydroxypropyl}-N³,N³- dipropylisophthalamide 331 180 “PHTH”N¹-{(1S,2R)-1-benzyl-3-[(4- MH + = chlorobenzyl)amino]-2- 537hydroxypropyl}-N³,N³- dipropylisophthalamide 332 181 “PHTH”N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + = {[2-(2-hydroxyethoxy) ethyl]500 amino}propyl)-N³,N³- dipropylisophthalamide 333 182 “PHTH”N¹-[(1S,2R)-1-benzyl-3-(2,3-dihydro- MH + = 1H-inden-1-ylamino)-2- 528hydroxypropyl]-N³,N³- dipropylisophthalamide 334 183 “PHTH”N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + =[(2-hydroxypropyl)amino]propyl}- 470 N³,N³-dipropylisophthalamide 335184 “PHTH” N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + = [(tetrahydro-2- 496furanylmethyl)amino]propyl}-N³,N³- dipropylisophthalamide 336 185 “PHTH”N¹-{(1S,2R)-1-benzyl-3-[(2,2- MH + = diethoxyethyl)amino]-2- 528hydroxypropyl} N³,N³- dipropylisophthalamide 337 186 “PHTH”N¹-[(1S,2R)-1-benzyl-3-(butylamino)- MH + = 2-hydroxypropyl]-N³,N³- 468dipropylisophthalamide 338 187 “PHTH” N¹-[(1S,2R)-1-benzyl-3- MH + =(cyclohexylamino)-2-hydroxypropyl]- 494 N³,N³-dipropylisophthalamide 339188 “PHTH” N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + =[(2-pyridinylmethyl)amino]propyl }- 507 N³,N³-dipropylisophthalamide 340189 “PHTH” N¹-{(1S,2R)-3-[(2- MH + = aminobenzyl)amino]-1-benzyl-2- 517hydroxypropyl}-N³,N³- dipropylisophthalamide 341 190 “PHTH”N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + =[(3-pyridinylmethyl)amino]propyl}- 503 N³,N³-dipropylisophthalamide 342191 “PHTH” N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + ={[2-(1-pyrrolidinyl)ethyl] amino} 509 propyl)-N³,N³-dipropylisophthalamide 343 192 “PHTH” N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-MH + = [(2-hydroxy-2- 532 phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide 344 193 “PHTH” N¹-{(1S,2R)-1-benzyl-3-[(3- MH + =butoxypropyl)amino]-2- 526 hydroxypropyl}-N³,N³- dipropylisophthalamide345 194 “PHTH” N¹-{(1S,2R)-1-beuzyl-2-hydroxy-3- MH + =[(3-isopropoxypropyl)amino]propyl}- 512 N³,N³-dipropylisophthalamide 346195 “PHTH” N¹-[(1S,2R)-1-benzyl-2-hydroxy-3- MH + =(isopentylamino)propyl]-N³,N³- 482 dipropylisophthalamide 347 196 “PHTH”N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + = [(3-phenylpropyl)amino]propyl}-530 N³,N³-dipropylisophthalamide 348 197 “PHTH”N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + = [(2-methoxyethyl)amino]propyl}-470 N³,N³-dipropylisophthalamide 349 198 “PHTH”N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + = [(2-phenoxyethyl)amino]propyl}-532 N³,N³-dipropylisophthalamide 350 199 “PHTH”N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + = [(2-propoxyethyl)amino]propyl}-498 N³,N³-dipropylisophthalamide 351 200 “PHTH”N¹-{(1S,2R)-1-benzyl-3-[(3,3- MH + = dimethylbutyl)amino]-2- 496hydroxypropyl}-N³,N³- dipropylisophthalamide 352 201 “PHTH”N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + = [(4-phenylbutyl)amino]propyl}-544 N³,N³-dipropylisophthalamide 353 202 “PHTH”N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + =[(3-iodobenzyl)amino]propyl}-N³,N³- 628 dipropylisophthalamide 354 203“PHTH” N¹-{(1S)-1-benzyl-2-hydroxy-3-[(4- MH + =nitrobenzyl)amino]propyl}-N³,N³- 547 dipropylisophthalamide 355 204“PHTH” N¹-{(1S,2R)-1-benzyl-3-[(3- MH + = chlorobenzyl)amino]-2- 537hydroxypropyl}-N³,N³- dipropylisophthalamide 356 205 “PHTH”N¹-((1S,2R)-1-benzyl-3-{[2-(4- MH + = chlorophenyl)ethyl]amino}-2- 551hydroxypropyl)-N³,N³- dipropylisophthalamide 357 206 “PHTH”N¹((1S,2R)-1-benzyl-2-hydroxy-3- MH + ={[2-(2-pyridinyl)ethyl]amino}propyl)- 517 N³,N³-dipropylisophthalamide358 207 “PHTH” N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + =[(4-pyridinylmethyl)amino]propyl}- 503 N³,N³-dipropylisophthalamide 359208 “PHTH” N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + = {[2-(1-methyl-2- 523pyrrolidinyl)ethyl]amino}propyl)- N³,N³-dipropylisophthalamide 360 209“PHTH” N¹-{(1S,2R)-1-benzyl-3-[(2,3- MH + = dimethylbenzyl)amino]-2- 580hydroxypropyl}-N³,N³- dipropylisophthalamide 361 210 “PHTH”N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + = {[2-(trifluoromethoxy) benzyl]586 amino}propyl)-N³,N³- dipropylisophthalamide 362 211 “PHTH”N¹-{(1S,2R)-1-benzyl-3-[(2-chloro-6- MH + = phenoxybenzyl)amino]-2- 629hydroxypropyl}-N³,N³- dipropylisophthalamide 363 212 “PHTH”N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + = {[4- 570(trifluoromethyl)benzyl]amino}propyl )-N³,N³-dipropylisophthalamide 364213 “PHTH” N¹-{(1S,2R)-1-benzyl-3-[(2,3- MH + = dichlorobenzyl)amino]-2-571 hydroxypropyl}-N³,N³- dipropylisophthalamide 365 214 “PHTH”N¹-{(1S,2R)-1-benzyl-3-[(3,5- MH + = dichlorobenzyl)amino]-2- 571hydroxypropyl}-N³,N³- dipropylisophthalamide 366 215 “PHTH”N¹⁻{(1S,2R)-1-benzyl-3-[(3,5- MH + = difluorobenzyl)amino]-2- 538hydroxypropyl}-N³,N³- dipropylisophthalamide 367 216 “PHTH”N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + = {[4- 586(trifluoromethoxy)benzyl]amino}prop- yl)-N³,N³-dipropylisophthalamide368 217 “PHTH” N¹-[(1S,2R)-3-({2-[4- MH + =(aminosulfonyl)phenyl]ethyl}amino)- 595 1-benzyl-2-hydroxypropyl]-N³,N³-dipropylisophthalamide 369 218 “PHTH” N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-MH + = [(4-methoxybenzyl)amino]propyl}- 532 N³,N³-dipropylisophthalamide370 219 “PHTH” N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + =[(4-methylbenzyl)amino]propyl}- 516 N³,N³-dipropylisophthalamide 371 220“PHTH” N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + = [(3,4,5- 592trimethoxybenzyl)amino]propyl}- N³,N³-dipropylisophthalamide 372 221“PHTH” N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + ={[3-(trifluoromethoxy)benzyl]amino} 586 propyl)-N³,N³-dipropylisophthalamide 373 222 “PHTH” N¹-{(1S,2R)-1-benzyl-3-[(3,5- MH += dimethoxybenzyl)amino]-2- 562 hydroxypropyl}-N³,N³-dipropylisophthalamide 374 223 “PHTH” N¹-{(1S,2R)-1-benzyl-3-[(2,4- MH += dimethoxybenzyl)amino]-2- 562 hydroxypropyl}-N³,N³-dipropylisophthalamide 375 224 “PHTH” N¹-{(1S,2R)-1-benzyl-3-[([1,1′-MH + = biphenyl]-3-ylmethyl)amino]-2- 578 hydroxypropyl}-N³,N³-dipropylisophthalamide 376 225 “PHTH” N¹-{(1S,2R)-1-benzyl-3-[(3,4- MH += dichlorobenzyl)amino]-2- 571 hydroxypropyl}-N³,N³-dipropylisophthalamide 377 226 “PHTH” N¹-{(1S,2R)-1-benzyl-3-[(2- MH + =fluorobenzyl)amino]-2- 520 hydroxypropyl}-N³,N³- dipropylisophthalamide378 227 “PHTH” N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + ={[3-(trifluoromethyl)benzyl]amino} 570 propyl)-N³,N³-dipropylisophthalamide 379 228 “PHTH” N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-MH + = [(2-methylbenzyl)amino]propyl}- 516 N³,N³-dipropylisophthalamide380 229 “PHTH” N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + ={[(1R)-1-phenylethyl]amino}propyl)- 516 N³,N³-dipropylisophthalamide 381230 “PHTH” N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + ={[(1S)-1-phenylethyl]amino}propyl)- 516 N³,N³-dipropylisophthalamide 382231 “PHTH” N¹-((1S,2R)-1-benzyl-3-{[3,5- MH + =bis(trifluoromethyl)benzyl]amino}-2- 638 hydroxypropyl)-N³,N³-dipropylisophthalamide 383 232 “PHTH” N¹-((1S,2R)-1-benzyl-2-hydroxy-3-MH + = {[2-(trifluoromethyl)benzyl]amino} 570 propyl)-N³,N³-dipropylisophthalamide 384 233 “PHTH” N¹-((1S,2R)-1-benzyl-2-hydroxy-3-MH + = {[(1S)-1-(1- 566 naphthyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide 385 234 “PHTH” N¹-((1S,2R)-1-benzyl-2-hydroxy-3-MH + = {[(1R)-1-(1- 566 naphthyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide 386 235 “PHTH” N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-MH + = [(4-hydroxy-3- 548 methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide 387 236 “PHTH”N¹-{(1S,2R)-1-benzyl-3-[(3,4- MH + = dihydroxybenzyl)amino]-2- 534hydroxypropyl}-N³,N³- dipropylisophthalamide 388 237 “PHTH”N¹-{(1S)-1-benzyl-2-hydroxy-3-[(3- MH + =methoxypropyl)amino]propyl}-N³,N³- 484 dipropylisophthalamide 389 238“PHTH” N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + = {[(1S)-2-hydroxy-1- 470methylethyl]amino}propyl)-N³,N³- dipropylisophthalamide 390 239 “PHTH”N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + = {[(1R)-2-hydroxy-1- 470methylethyl]amino}propyl)-N³,N³- dipropylisophthalamide 391 240 “PHTH”N¹-[(1S,2R)-1-benzyl-2-hydroxy-3- MH + = (2-propynylamino)propyl]-N³,N³-450 dipropylisophthalamide 392 241 “PHTH” N¹-((1S,2R)-1-benzyl-3-{[2-(2-MH + = fluorophenyl)ethyl]amino}-2- 534 hydroxypropyl)-N³,N³-dipropylisophthalamide 393 242 “PHTH” N¹-((1S,2R)-1-benzyl-3-{[2-(3-MH + = fluorophenyl)ethyl]amino}-2- 534 hydroxypropyl)-N³,N³-dipropylisophthalamide 394 243 “PHTH” N¹-((1S,2R)-1-benzyl-3-{[2-(4-MH + = fluorophenyl)ethyl]amino}-2- 534 hydroxypropyl)-N³,N³-dipropylisophthalamide 395 244 “PHTH” N¹-((1S,2R)-1-benzyl-3-{[2-(4-MH + = bromophenyl)ethyl]amino}-2- 595 hydroxypropyl)-N³,N³-dipropylisophthalamide 396 245 “PHTH” N¹-((1S)-1-benzyl-2-hydroxy-3-{[2-MH + = (3- 546 methoxyphenyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide 397 246 “PHTH”N¹-((1S,2R)-1-benzyl-3-{[2-(2,4- MH + = dichlorophenyl)ethyl]amino}-2-585 hydroxypropyl)-N³,N³- dipropylisophthalamide 398 247 “PHTH”N¹-((1S,2R)-1-benzyl-3-{[2-(3- MH + = chlorophenyl)ethyl]amino}-2- 551hydroxypropyl)-N³,N³- dipropylisophthalamide 399 248 “PHTH”N¹-((1S)-1-benzyl-3-{[2-(2,5- MH + = dimethoxyphenyl)ethyl]amino}-2- 576hydroxypropyl)-N³,N³- dipropylisophthalamide 400 249 “PHTH”N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + = {[2-(4- 530methylphenyl)ethyl]amino}propyl)- N³,N³-dipropylisophthalamide 401 250“PHTH” N¹-((1S,2R)-1-benzyl-3-{[(1R)-1- MH + =benzyl-2-hydroxyethyl]amino}-2- 546 hydroxypropyl)-N³,N³-dipropylisophthalamide 402 251 “PHTH” N¹-((1S,2R)-1-benzyl-2-hydroxy-3-MH + = {[3-(4- 539 morpholinyl)propyl]amino}propyl)-N³,N³-dipropylisophthalamide 403 252 “PHTH”N¹-[(1S,2R)-1-benzyl-2-hydroxy-3- MH + = (isobutylamino)propyl]-N³,N³-468 dipropylisophthalamide 404 253 “PHTH”N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + = {[2-(4- 525morpholinyl)ethyl]amino}propyl)- N³,N³dipropylisophthalamide 405 254“PHTH” N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH + =[(2-hydroxybutyl)amino]propyl}- 484 N³,N³dipropylisophthalamide 406 255“PHTH” N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + ={[2-(2-thienyl)ethyl]amino}propyl)- 522 N³,N³-dipropylisophthalamide 407256 “PHTH” N¹{(1S,2R)-1-benzyl-2-hydroxy-3- MH + =[(4-hydroxybutyl)amino]propyl}- 484 N³,N³-dipropylisophthalamide 408 257“PHTH” N¹((1S,2R)-1-benzyl-2-hydroxy-3- MH + = {[(1S)-2-hydroxy-1- 532phenylethyl]amino}propyl)-N³,N³- dipropylisophthalamide 409 258 “PHTH”N¹-{(1S,2R)-1-benzyl-3-[(2,4- MH + = dichlorobenzyl)amino]-2- 571hydroxypropyl}-N³,N³- dipropylisophthalamide 410 259 “PHTH”N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH + = {[(1R)-2-hydroxy-1- 532phenylethyl]amino}propyl)-N³,N³- dipropylisophthalamide 411 260 “PHTH”N¹-{(1S,2R)-1-benzyl-3-[(4-tert- MH⁺ = butylbenzyl)amino]-2- 558hydroxypropyl}-N³,N³- dipropylisophthalamide 412 261 “PHTH”N¹-{(1S,2R)-1-benzyl-2-hydroxy-3- MH⁺ = [(1-phenylethyl)amino]propyl}-516 N³,N³-dipropylisophthalamide 413 262 “PHTH”N¹-((1S,2R)-1-benzyl-2-hydroxy-3- MH⁺ ={[(1R,2S)-2-hydroxy-2,3-dihydro-1H- 544 inden-1-yl]amino}propyl)-N³,N³-dipropylisophthalamide 414 263 “PHTH” N¹-{(1S,2R)-1-benzyl-3-[(3,4- MH⁺= dimethylbenzyl)amino]-2- 530 hydroxypropyl}-N³,N³-dipropylisophthalamide 416 265 “PHTH”N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-{[2-(isobutylamino)-1- 575 methyl-2-oxoethyl]amino}propyl)-N³,N³-dipropylisophthalamide 417 266 “PHTH”N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-{[(1S)-2-(isobutylamino)- 5751-methyl-2-oxoethyl]amino}propyl)- N³,N³-dipropylisophthalamide 418 266“3,5-pyridinyl” N³-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-{[(1S)-2-(isobutylamino)- 5761-methyl-2-oxoethyl]amino}propyl)- N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide 419 267 “5-Me-PHTH”N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-{[2-(isobutylamino)-1,1- 603dimethyl-2-oxoethyl]amino}propyl)- 5-methyl-N³,N³-dipropylisophthalamide 420 268 “5-Me-PH”N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-{[2-(isobutylamino)-2- 575.3 oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide 421 269 “5-Me-PHTH”N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2- MH + = hydroxy-3-({(1S)-1- 603.8[(isobutylamino)carbonyl]propyl}ami- no)propyl]-5-methyl-N³,N³-dipropylisophthalamide 422 270 “5-Me-PHTH”N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2- MH + = hydroxy-3-({(1R)-1- 603.8[(isobutylamino)carbonyl]propyl}ami- no)propyl]-5-methyl-N³,N³-dipropylisophthalamide 423 271 “5-Me-PHTH”N¹-[(1S,2R)-3-(benzylamino)-1-(3,5- MH + =difluorobenzyl)-2-hydroxypropyl]-5- 552.3methyl-N³,N³-dipropylisophthalamide 424 272 “5-Me-PHTH”N¹[(1S,2R)-1-(3,5-difluorobenzyl)-3- MH + =(ethylamino)-2-hydroxypropyl]-5- 490.7methyl-N³,N³-dipropylisophthalamide 425 273 “5-Me-PHTH”N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-(isobutylamino)propyl]-5- 518.0methyl-N³,N³-dipropylisophthalamide 426 274 “5-Me-PHTH”N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-{[3-(isobutylamino)-2- 603 methyl-3-oxopropyl]amino}propyl)-5-methyl-N³,N³- dipropylisophthalamide 427 275 “5-Me-PHTH”N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3- MH + ={[4-(dimethylamino)benzyl]amino}- 595.8 2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide 428 276 “5-Me-PHTH”N¹-[(1S,2R)-3-{[(1S)-1-benzyl-2- MH + =(isobutylamino)-2-oxoethyl]amino}- 665.9 1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³- dipropylisophthalamide 429 277“5-Me-PHTH” N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-({(1S)-1- 617.9 [(isobutylamino)carbonyl]-2-methylpropyl}amino)propyl]-5- methyl-N³,N³-dipropylisophthalamide 430278 “5-Me-PHTH” N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3- MH + ={[2-(dimethylamino)ethyl]amino}-2- 533.3 hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide 431 279 “5-Me-PHTH”N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + = 2-hydroxy-3-[(3- 553pyridinylmethyl)amino]propyl}-5- methyl-N³,N³-dipropylisophthalamide 432280 “5-Me-PHTH” N¹-[(1S,2R)-3-{[(1S)-1- MH + = [(benzyloxy)methyl]-2-695.9 (isobutylamino)-2-oxoethyl]amino}- 1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³- dipropylisophthalamide 433 281“5-Me-PHTH” N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + =2-hydroxy-3-[(1-methyl-1- 580.8 phenylethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide 434 282 “5-Me-PHTH”N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2- MH + = hydroxy-3-({(1R)-1- 617.9[(isobutylamino)carbonyl]-2- methylpropyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide 435 283 “5-Me-PHTH”N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2- MH + = hydroxy-3-({(1S)-1- 617.9[(isobutylamino)carbonyl]butyl}amino) propyl]-5-methyl-N³,N³-dipropylisophthalamide 436 284 “5-Me-PHTH”N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-{[(1S)-1-(hydroxymethyl)- 605.8 2-(isobutylamino)-2-oxoethyl]amino}propyl)-5-methyl N³,N³-dipropylisophthalamide 437 285“5-Me-PHTH” N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + = 2-hydroxy-3-[(2-566.8 phenylethyl)amino]propyl}-5-methyl- N³,N³-dipropylisophthalamide438 286 “5-Me-PHTH” N¹-[(1S,2R)-3-{[(1S)-2- MH + =(benzylamino)-1-methyl-2- 623.2 oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5- methyl-N³,N³-dipropylisophthalamide439 287 “5-Me-PHTH” N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-{[(1S)-1- 580.8 phenylpropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide 440 287a “5-Me-PHTH”N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3- MH + ={[(1S)-2-(ethylamino)-1-methyl-2- 561.2oxoethyl]amino}-2-hydroxypropyl)- 5-methyl-N³,N³- dipropylisophthalamide441 289 “5-Me-PHTH” N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-{[(1S)-2-(isobutylamino)- 651.92-oxo-1-phenylethyl]amino}propyl)- 5-methyl-N³,N³-dipropylisophthalamide 442 290 “5-Me-PHTH”N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-(isopentylamino)propyl]- 531.69 5-methyl-N³,N³-dipropylisophthalamide 443 291 “5-Me-PHTH”N¹-[(1S,2R)-3-(cyclohexylamino)-1- MH + = (3,5-difluorobenzyl)-2- 544.2hydroxypropyl]-5-methyl-N³,N³- dipropylisophthalamide 444 292“5-Me-PHTH” N¹-[(1S,2R)-3-(butylamino)-1-(3,5- MH + =difluorobenzyl)-2-hydroxypropyl]-5- 518.2methyl-N³,N³-dipropylisophthalamide 445 293 “5-Me-PHTH”N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + = 2-hydroxy-3-[(3- 534.2methoxypropyl)amino]propyl}-5- methyl-N³,N³-dipropylisophthalamide 446294 “5-Me-PHTH” N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + =2-hydroxy-3-[(2-hydroxy-2- 582 phenylethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide 447 295 “5-Me-PHTH”N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3- MH + = {[(3R,5S)-3,5- 604.2dimethoxycyclohexyl]amino}-2- hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide 448 296 “5-Me-PHTH” dimethyl(1R,3S)-5-{[(2R,3S)-4-(3,5- MH + = difluorophenyl)-3-({3- 660.2[(dipropylamino)carbonyl]-5- methylbenzoyl}amino)-2-hydroxybutyl]amino}-1,3- cyclohexanedicarboxylate 449 297 “5-Me-PHTH”(1R,3S)-5-{[(2R,3S)-4-(3,5 MH + = difluorophenyl)-3-({3- 632.2[(dipropylamino)carbonyl]-5- methylbenzoyl}amino)-2-hydroxybutyl]amino}-1,3- cyclohexanedicarboxylic acid 450 298“5-Me-PHTH” N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-{[(1R)-1- 580.8 phenylpropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide 451 299 “5-Me-PHTH”N¹-[(1S,2R)-3-[(3- MH + = chlorobenzyl)amino]-1-(3,5- 586.3difluorobenzyl)-2-hydroxypropyl]-5- methyl-N³,N³-dipropylisophthalamide452 300 “-SO₂-” N-{(1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-[(3- 603.2 methoxybenzyl)amino]propyl}-3-[(2-propylpentyl)sulfonyl]benzamide 453 301 “5-Me-PHTH”N¹{(1S,2R)-3-[([1,1′-biphenyl]-3- MH + = ylmethyl)amino]-1-(3,5- 628.8difluorobenzyl)-2-hydroxypropyl]-5- methyl-N³,N³-dipropylisophthalamide454 302 “5-Me-PHTH” N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + =2-hydroxy-3-[(3- 678 iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide 455 303 “5-Me-PHTH”N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + = 2-hydroxy-3-[(3- 566.8methylbenzyl)amino]propyl}-5- methyl-N³,N³-dipropylisophthalamide 456304 “5-Me-PHTH” N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + =2-hydroxy-3-[(2- 694 phenylpropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide 457 305 “5-Me-PHTH”N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + = 2-hydroxy-3-[(1,3-thiazol-5-559.5 ylmethyl)amino]propyl}-5-methyl- N³,N³-dipropylisophthalamide 458306 “5-Me-PHTH” N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + =2-hydroxy-3-[(2- 558.5 thienylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide 459 307 “5-Me-PHTH”N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + =2-hydroxy-3-[(5-methoxy-1,2,3,4- 814 tetrahydro-1-naphthalenyl)amino]propyl}-5- methyl-N³,N³-dipropylisophthalamide 460308 “5-Me-PHTH” N¹-((1S,2R)-1-(3,5-difluorobenzyl)- MH + =2-hydroxy-3-[(2- 554.3 pyrazinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide 461 309 “5-Me-PHTH”N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + =3-[(3,5-difluorobenzyl)amino]-2- 588.7 hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide 462 310 “PHTH” N¹-{(1S,2R)-3-[(1,3-benzodioxol-5-MH + = ylmethyl)amino]-1-benzyl-2- 546 hydroxypropyl}-N³,N³-dipropylisophthalamide 463 311 “5-Me-PHTH”N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + =3-[(3,5-dimethoxybenzyl)amino]-2- 612.4 hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide 464 312 “5-Me-PHTH”N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + = hydroxy-3-{[3- 620.3(trifluoromethyl)benzyl]amino}propyl )-5-methyl-N³,N³-dipropylisophthalamide 466 314 “5-Me-PHTH” Racemic N¹-{(1S,2R)-1-(3,5-MH+ = difluorobenzyl)-2-hydroxy-3-[(7 814 methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5- methyl-N³,N³-dipropylisophthalamide 467315 “5-Me-PHTH” N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-{[3- 636.3 (trifluoromethoxy)benzyl]amino}prop-yl)-5-methyl-N³,N³- dipropylisophthalamide 468 316 “5-Me-PHTH”N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + = 3-[(3-fluorobenzyl)amino]-2-570.3 hydroxypropyl}-5-methyl-N³,N³- dipropylisophthalamide 469 317“5-Me-PHTH” N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + = 2-hydroxy-3-[(3-610.4 isopropoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide 470 318 “5-Me-PHTH”N¹-[(1S,2R)-3-[(3- MH + = bromobenzyl)amino]-1-(3,5- 631.6difluorobenzyl)-2-hydroxypropyl]-5- methyl-N³,N³-dipropylisophthalamide471 319 “5-Me-PHTH” N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2- MH + =hydroxy-3-{[(5-methyl-2- 556 furyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide 472 320 “5-Me-PHTH”N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH + =2-hydroxy-3-[(5-methoxy-1,2,3,4- 622 tetrahydro-1-naphthalenyl)amino]propyl}-5- methyl-N³,N³-dipropylisophthalamide“isomer A” 473 320 “5-Me-PHTH” N¹-{(1S,2R)-1-(3,5-difluorobenzyl)- MH⁺ =2-hydroxy-3-[(5-methoxy-1,2,3,4- 622 tetrahydro-1-naphthalenyl)amino]propyl}-5- methyl-N³,N³-dipropylisophthalamide“isomer B”

Example 474N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(1,2,3,4-tetrahydro-1-naphthalenylamino)propyl]-N³,N³-dipropylisophthalamide(X)

Following the general procedures of EXAMPLEs 6 and 321–473 and makingnon-critical variations but starting with(2R,3S)-3-amino-4-phenyl-1-(1,2,3,4-tetrahydro-1-naphthalenylamino-2-butanol(VIII) and using “PHTH”, the title compound is obtained, MH⁺=542.3.

Examples 475–483

Following the general procedure of EXAMPLE 6 and making non-criticalvariations but starting with the amine (VIII) of Column A and reactingit with the amide forming agent (IX) of Column B, the substitute amine(X) of Column C is obtained.

Column A Amine (VIII) Column B Column D Compound Amide Forming Column CPhysical EXA of EXA Agent (IX) Substitued amine (X) Data 475 271“5-OMe-PHTH” N¹-[(1S,2R)-3-(benzylamino)-1-(3,5- MH⁺ =difluorobenzyl)-2-hydroxypropyl]-5- 568.2 methoxy-N³,N³-dipropylisophthalamide 476 271 “PHTH”N¹-[(1S,2R)-3-(benzylamino)-1-(3,5- MH⁺ =difluorobenzyl)-2-hydroxypropyl]- 538.2 N³,N³-dipropylisophthalamide 477271 “5-Cl-PHTH” N¹-[(1S,2R)-3-(benzylamino)-1-(3,5- MH⁺ =difluorobenzyl)-2-hydroxypropyl]-5- 572.1chloro-N³,N³-dipropylisophthalamide 478 271 “3,5-pyridinyl”N³-[(1S,2R)-3-(benzylamino)-1-(3,5- MH⁺ =difluorobenzyl)-2-hydroxypropyl]- 539.5 N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide 479 271 “5-F-PHTH”N¹-[(1S,2R)-3-(benzylamino)-1-(3,5- MH⁺ =difluorobenzyl)-2-hydroxypropyl]-5- 556.3fluoro-N³,N³-dipropylisophthalamide 480 271 “thienyl”N²-[(1S,2R)-3-(benzylamino)-1-(3,5- MH⁺ =difluorobenzyl)-2-hydroxypropyl]- 544.2 N⁵,N⁵-dipropyl-2,5-thiophenedicarboxamide 481 271 “2,4-pyridinyl”N⁴-[(1S,2R)-3-(benzylamino)-1-(3,5- MH⁺ =difluorobenzyl)-2-hydroxypropyl- 539.3 N²,N²-dipropyl-2,4-pyridinedicarboxamide 482 271 “4,6- N⁴-[(1S,2R)-3-(benzylamino)-1-(3,5-MH + = pyrimidinyl” difluorobenzyl)-2-hydroxypropyl]- 540N⁶,N⁶dipropyl-4,6- pyrimidinedicarboxamide 483 271 “morpholinyl”N-[(1S,2R)-3-(benzylamino)-1-(3,5- MH + =difluorobenzyl)-2-hydroxypropyl]-3- 552 (4-morpholinylcarbonyl)benzamide

Example 484N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-N³,N³-dipropylisophthalamide(X)

Following the general procedures of EXAMPLEs 4 and 14–107 and makingnon-critical variations but starting with tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V, commercially available) andNH₂—CH₂-phenyl-(3-CH₃) (VI), the corresponding protected alcohol (VII)is obtained.

Following the general procedure of EXAMPLEs 5 and 170–320 and makingnon-critical variations, the corresponding amine (VIII) is obtained.

Following the general procedure of EXAMPLEs 6 and 321–483 and makingnon-critical variations but using “PHTH” (IX), the title compound isobtained, MH⁺=516.

Example 485N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide(X)

Following the general procedure of EXAMPLEs 6 and making non-criticalvariations and using(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol(VIII, EXAMPLE 5) with 5-(dipropylamino)-5-oxopentanoic acid (DX), thetitle compound is obtained, MH⁺=534.2.

Example 486N¹-[(1S,2R)-3-{[(1R)-1-[(benzyloxy)methyl]-2-(isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedures of EXAMPLEs 124, 280 and 432 and makingnon-critical variations but using the “R” C-terminal amine (VI), thetitle compound is obtained, MH⁺=695.

Example 487N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R)-1-(hydroxymethyl)-2-(isobutylamino)-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedures of EXAMPLEs 128, 284 and 436 and makingnon-critical variations but using the “R” C-terminal amine (VI), thetitle compound is obtained, MH⁺=719.

Example 488N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(pentylamino)propyl]-N³,N³-dipropylisophthalamide(X)

Following the general procedures of EXAMPLEs 96, 252 and 403 and makingnon-critical variations but using NH₂—(CH₂)₄—CH₃ as the C-terminal amine(VI), the title compound is obtained, MH⁺=481.

Example 489N¹-[(1S)-3-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-1-benzyl-2-hydroxypropyl]-N³,N³-dipropylisophthalamide(X)

Following the general procedures of EXAMPLEs 61, 217 and 368 and makingnon-critical variations but using racemic C-terminal amine (VI), thetitle compound is obtained, MH⁺=595.

Example 491N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1,3-thiazol-5-ylmethyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide(X)

Following the general procedure of EXAMPLE 457 and making non-criticalvariations and using(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(1,3-thiazol-5-ylmethyl)amino]-2-butanol(VIII, EXAMPLE 305) with “3,5-pyridinyl” as the amide forming agent(IX), the title compound is obtained.

Example 4923-Benzoyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}benzamide(X)

Following the general procedure of EXAMPLE 452 and making non-criticalvariations and using(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanoltrifluoroacetate (VIII, EXAMPLE 5) and reacting it withphenyl-CO-phenyl-CO—OH (IX) where the attachment to the -phenyl-ring is1,3- for the carbonyl groups, the title compound is obtained, MH⁺=545.2.

Example 493N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}[1,1′-biphenyl]-3-carboxamide(X)

Following the general procedure of EXAMPLE 452 and making non-criticalvariations and using(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanoltrifluoroacetate (VIII, EXAMPLE 5) and reacting it withphenyl-phenyl-CO—OH (IX) where the attachment to the middle- phenyl-ringis 1,3- for the carbonyl group and other- phenyl , the title compound isobtained, MH⁺=517.2.

Example 494N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLE 452 and making non-criticalvariations and using(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanoltrifluoroacetate (VIII, EXAMPLE 5) and reacting it with(CH₃—O—CH₂—CH₂—)₂N—CO—CO—OH (IX) where the attachment to the-phenyl-ring is 1,3- for the carbonyl groups, the title compound isobtained, MH⁺=570.3.

Example 495N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³-(2-methoxyethyl)-N3-propylisophthalamide(X)

Following the general procedure of EXAMPLE 452 and making non-criticalvariations and using(2R,3S)-3-amino-1-(benzylamino)-4-(3,5-difluorophenyl)-2-butanol (VIII,EXAMPLE 271) and reacting it with(CH₃—CH₂—CH₂—)(CH₃—O—CH₂—CH₂—)N—CO-phenyl-CO—OH (IX) where theattachment to the -phenyl-ring is 1,3- for the carbonyl groups, thetitle compound is obtained, MH⁺=554.5.

Example 496N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-ethoxybenzamide(X)

Following the general procedure of EXAMPLE 452 and making non-criticalvariations and using(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanoltrifluoroacetate (VIII, EXAMPLE 5) and reacting it withCH₃—CH₂—O-phenyl-CO—OH (IX) where the attachment to the -phenyl-ring is1,3- for the carbonyl and ethoxy group, the title compound is obtained,MH⁺=485.

Example 497N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-naphthamide(X)

Following the general procedure of EXAMPLE 452 and making non-criticalvariations and using(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanoltrifluoroacetate (VIII, EXAMPLE 5) and reactinortho position, the titlecompound is obtained, MH⁺=491.

Example 498N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1R)-1,2,3,4-tetrahydro-1-naphthalenylamino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), 1,2,3,4-tetrahydro-1-naphthalenylamine (VI) and “5-Me-PHTH” (IX),the title compound is obtained, MH⁺=588.

Example 499N¹-[(1R)-3-{[3,5-bis(trifluoromethyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), H₂N—CH₂-phenyl-(3,5-ditrifluoromethyl) (VI) and “5-Me-PHTH” (IX),the title compound is obtained, MH⁺=688.

Example 500N¹-((1S,2R)-1-benzyl-3-{[2-fluoro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V),H₂N—CH₂-phenyl-(2-fluoro-5-trifluoromethyl) (VI) and “PHTH” (IX), thetitle compound is obtained, MH⁺=588.

Example 501N¹-{(1S,2R)-1-benzyl-3-[(2,3-difluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), H₂N—CH₂-phenyl-(2,3-difluoro)(VI) and “PHTH” (IX), the title compound is obtained, MH⁺=538.

Example 502N¹-((1S,2R)-1-benzyl-3-{[3-fluoro-4-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V),H₂N—CH₂-phenyl-(3-fluoro-4-trifluoromethyl) (VI) and “PHTH” (IX), thetitle compound is obtained, MH⁺=588.

Example 503N¹-{(1S,2R)-1-benzyl-3-[(2,5-difluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), H₂N—CH₂-phenyl-(2,5-difluoro)(VI) and “PHTH” (IX), the title compound is obtained, MH⁺=538.

Example 504N¹-((1S,2R)-1-benzyl-3-{[3-fluoro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V),H₂N—CH₂-phenyl-(3-fluoro-5-trifluoromethyl) (VI) and “PHTH” (IX), thetitle compound is obtained, MH⁺=588.

Example 505N¹-{(1S,2R)-1-benzyl-3-[(3,4-difluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), H₂N—CH₂-phenyl-(3,4-difluoro)(VI) and “PHTH” (IX), the title compound is obtained, MH⁺=538.

Example 506N¹-((1S,2R)-1-benzyl-3-{[4-fluoro-3-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V),H₂N—CH₂-phenyl-(3-trifluoromethyl4-fluoro) (VI) and “PHTH” (IX), thetitle compound is obtained, MH⁺=588.

Example 507N¹-((1S,2R)-1-benzyl-3-{[2-chloro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V),H₂N—CH₂-phenyl-(2-chloro-5-trifluoromethyl) (VI) and “PHTH” (IX), thetitle compound is obtained, MH⁺=605.

Example 508N¹-((1S,2R)-1-benzyl-3-{[4-chloro-3-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V),H₂N—CH₂-phenyl-(3-trifluoromethyl-4-chloro) (VI) and “PHTH” (IX), thetitle compound is obtained, MH⁺=605.

Example 509N¹-[(1S,2R)-1-benzyl-3-(2,3-dihydro-1H-inden-2-ylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V),H₂N—(2,3-dihydro-1H-inden-2-yl) and “PHTH” (IX), the title compound isobtained, MH⁺=528.

Example 510N¹-{(1S)-1-benzyl-2-hydroxy-3-[(3-nitrobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), H₂N—CH₂-phenyl-3-nitro (VI)and “PHTH” (IX), the title compound is obtained, MH⁺=547.

Example 511N¹-((1S,2R)-1-benzyl-3-{[3-(difluoromethoxy)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), H₂N—CH₂-phenyl-3(-O—CHF₂)(VI) and “PHTH” (IX), the title compound is obtained, MH⁺=538.

Example 512N¹-{(1S,2R)-1-benzyl-3-[(3-ethoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), H₂N—CH₂-phenyl-(3—O—CH₂—CH₃)(VI) and “PHTH” (IX), the title compound is obtained, MH⁺=546.

Example 513N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(5-methyl-2-pyrazinyl)methyl]amino}propyl)-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 5-methyl-2-methylaminoprazine(VI) and “PHTH” (IX), the title compound is obtained, MH⁺=518.

Example 514N¹-{(1S,2R)-1-benzyl-3-[(3-bromo-4-fluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V),H₂N—CH₂-phenyl-(3-bromo-4-fluoro) (VI) and “PHTH” (IX), the titlecompound is obtained, MH⁺=599.

Example 515N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,5-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),H₂N—CH₂-phenyl-(3,5-dimethyl) (VI) and “5-Me-PHTH” (IX), the titlecompound is obtained, MH⁺=580.

Example 516N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethoxybenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),H₂N—CH₂-phenyl-(3-ethoxy) (VI) and “5-Me-PHTH” (IX), the title compoundis obtained, MH⁺=596.

Example 517N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),H₂N—CH₂—CH₂—O-phenyl (VI) and “5-Me-PHTH” (IX), the title compound isobtained, MH⁺=582.

Example 518N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isobutoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),H₂N—CH₂-phenyl-O-i-butyl (VI) and “5-Me-PHTH” (IX), the title compoundis obtained, MH⁺=624.

Example 519N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-methyl-1,3-thiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),H₂N—CH₂-4-methyl-1,3-thiazol-2-yl (VI) and “5-Me-PHTH” (IX), the titlecompound is obtained, MH⁺=573.

Example 520N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³-methyl-N³-propylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),H₂N—CH₂-phenyl (VI) and (CH₃—CH₂—CH₂—)(CH₃—)N—CO—(CH₃—)phenyl-CO—OH (IX)where the attachment to the -phenyl-ring for the carbonyls is 1-,3- and5- for the methyl group, the title compound is obtained, MH⁺=510.

Example 521N²-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N⁵,N⁵-dipropyl-2,5-furandicarboxamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),H₂N—CH₂-phenyl (VI) and (CH₃—CH₂—CH₂—)₂N—CO—(2,5-furanyl)—CO— (IX), thetitle compound is obtained, MH⁺=528.

Example 522N³-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide(X)

Following the general procedure of EXAMPLEs 4,5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),H₂N—CH₂-phenyl-3-trifluoromethyl (VI) and “3,5-pyridinyl” (IX), thetitle compound is obtained, MH⁺=607.

Example 523N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),H₂N—C(—CH₃)₂-phenyl (VI) and “3,5-pyridinyl” (IX), the title compound isobtained, MH⁺=567.

Example 524N¹-[(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of CHARTs A, C and D and EXAMPLEs165–168 and making non-critical variations, but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V) and“5-Me-PHTH” (IX), the title compound is obtained, MH⁺=462.

Example 525N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(1,2-diphenylethyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V), NH₂—CH()—CH₂-phenyl (VI) and “5-Me-PHTH” (IX), the title compound is obtained,MH⁺=642.

Example 526N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,isomer A (X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),7-methoxy-1,2,3,4-tetrahydro-1-naphthalenylamine (VI) and “5-Me-PHTH”(IX), the title compound is obtained, MH⁺=622.

Example 527N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,isomer B (X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),7-methoxy-1,2,3,4-tetrahydro-1-naphthalenylamine (VI) and “5-Me-PHTH”(IX), the title compound is obtained, MH⁺=622.

Example 528Benzyl-(1S,2R)-3-azido-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate(XII)

Following the general procedure of EXAMPLE 165 and making non-criticalvariations but starting with benzyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE13), the title compound is obtained.

Example 529N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(dimethylamino)benzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3-dimethylaminobenzoic acid (IX), the title compound is obtained,MH⁺=448.

Example 530N-[(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl]-2-methyl-1H-benzimidazole-5-carboxamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and2-methyl-1H-benzimidazole-5-carboxylic acid (IX), the title compound isobtained, MH⁺=459.

Example 5313-(aminosulfonyl)-N-{(1S)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-chlorobenzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3-(aminosulfonyl)-4-chlorobenzoic acid (IX), the title compound isobtained, MH⁺=519.

Example 532N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-cyanobenzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3-cyanobenzoic acid (IX), the title compound is obtained, MH⁺=430.

Example 533N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]-propyl}-4-chloro-3-nitrobenzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and4-chloro-3-nitrobenzoic acid (IX), the title compound is obtained,MH⁺=484.

Example 534 Methyl3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-nitrobenzoate(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3-nitro-5-(methyl-O—CO—)-phenyl-CO—OH (IX), the title compound isobtained, MH⁺=508.

Example 535 tert-butyl3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-phenylcarbamate(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3-(t-butyl-O—CO—NH)-phenyl-CO—OH (IX), the title compound is obtained,MH⁺=520.

Example 536N-[(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl]-9,10-dioxo-9,10-dihydro-2-anthourancenylcarboxamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and9,10-dioxo-9,10-dihydro-2-anthourancenylcarboxylic acid (IX), the titlecompound is obtained, MH⁺=535.

Example 537N-[(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl]-1H-1,2,3-benzotriazole-6-carboxamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and1H-1,2,3-benzotriazolyl-6-carboxylic acid (IX), the title compound isobtained, MH⁺=446.

Example 538N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and4-(3-methyl-5-oxo4,5-dihydro-1H-pyrazol-1-yl)benzoic acid (IX), thetitle compound is obtained, MH⁺=501.

Example 539N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]-propyl}-1H-indole-5-carboxamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) andindole-5-carboxylic acid (IX), the title compound is obtained, MH⁺=444.

Example 540N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-fluoro-5-(trifluoromethyl)benzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3-fluoro-5-(trifluoromethyl)benzoic acid (IX), the title compound isobtained, MH⁺=491.

Example 541N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]-propyl}-3-(trifluoromethyl)benzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3-(trifluoromethyl)benzoic acid (IX), the title compound is obtained,MH⁺=473.

Example 542N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]-propyl}-4-(butylamino)benzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and4-(butylamino)benzoic acid (IX), the title compound is obtained,MR⁺=476.

Example 543N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]-propyl}-3-(trifluoromethoxy)benzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3-(trifluoromethoxy)benzoic acid (IX), the title compound is obtained,MH⁺=489.

Example 544N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]-propyl}-3,5-dimethoxybenzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3,5-dimethoxybenzoic acid (IX), the title compound is obtained, MH⁺=465.

Example 545N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]-propyl}-3,5-dimethylbenzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3,5-dimethylbenzoic acid (IX), the title compound is obtained, MH⁺=433.

Example 546N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]-propyl}-3,5-difluorobenzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3,5-difluorobenzoic acid (IX), the title compound is obtained, MH⁺=441.

Example 547N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]-propyl}-3,5-dichlorobenzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3,5-dichlorobenzoic acid (IX), the title compound is obtained, MH⁺=474.

Example 548N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]-propyl}-4-(benzyloxy)benzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and4-(benzyloxy)benzoic acid (IX), the title compound is obtained, MH⁺=511.

Example 549N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]-propyl}-1,3-benzodioxole-5-carboxamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and1,3-benzodioxole-5-carboxylic acid (IX), the title compound is obtained,MH⁺=449.

Example 5503-(acetylamino)-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}benzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3-(acetylamino)benzoic acid (IX), the title compound is obtained,MH⁺=462.

Example 5514-(acetylamino)-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}benzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and4-(acetylamino)benzoic acid (IX), the title compound is obtained,MH⁺=462.

Example 552N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3,5-dimethyl-4-isoxazolyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), 3,5-dimethyl4-isoxazolylmethylamine (VI) and “5-Me-PHTH” (IX), thetitle compound is obtained, MH⁺=571.3.

Example 553N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-phenylpropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), 3-phenylpropyl)amine (VI) and “5-Me-PHTH” (IX), the title compoundis obtained, MH⁺=580.

Example 554N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-furylmethyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), 3-furylmethylamine (VI) and “5-Me-PHTH” (IX), the title compound isobtained, MH⁺=542.

Example 555N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(tetrahydro-3-furanylmethyl)amino]propyl}-5-methyl-N3,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), (tetrahydro-3-furanylmethyl)amine (VI) and “5-Me-PHTH” (IX), thetitle compound is obtained, MH+546.

Example 556N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-propoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), (3-propoxybenzyl)amine (VI) and “5-Me-PHTH” (IX), the title compoundis obtained, MH⁺=610.

Example 557N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-pyridinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), (2-pyridinylmethyl)amine (VI) and “5-Me-PHTH” (IX), the titlecompound is obtained, MH⁺=553.

Example 558N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-hydroxy-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), benzylamine (VI) and 5-hydroxy-N,N-dipropylisophthalic acid (IX),the title compound is obtained, MH⁺=554.

Example 559N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-methyl-1-(3-methylphenyl)ethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), [1-methyl-1-(3-methylphenyl)ethyl]amine (VI) and “5-Me-PHTH” (IX),the title compound is obtained, MH⁺=594.

Example 560N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylamino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine (VI) and “5-Me-PHTH”(IX), the title compound is obtained, MH⁺=592.

Example 561N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2,5-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), 2,5-dimethylbenzylamine (VI) and “5-Me-PHTH” (IX), the titlecompound is obtained, MH⁺=580.

Example 562N¹-[(1S,2R)-3-{[2-chloro-5-(trifluoromethyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), 2-chloro-5-trifluorobenzylamine (VI) and “5-Me-PHTH” (IX), the titlecompound is obtained, MH⁺=654.

Example 563N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-hydroxy-5-methylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), 2-hydroxy-5-methylbenzylamine (VI) and “5-Me-PHTH” (IX), the titlecompound is obtained, MH⁺=582.

Example 564N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amine (VI) and“5-Me-PHTH” (IX), the title compound is obtained, MH⁺=594.

Example 565N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), (1R)-2,3-dihydro-1H-inden-1-ylamine (VI) and “5-Me-PHTH” (IX), thetitle compound is obtained, MH⁺=578.

Example 5665-chloro-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), (1-methyl-1-phenylethyl)amine (VI) and “5-Cl-PHTH” (IX), the titlecompound is obtained, MH⁺=601.

Example 567N¹-[(1S,2R)-3-[(1-benzofuran-2-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), (1-benzofuran-2-ylmethyl)amine (VI) and “5-Me-PHTH” (IX), the titlecompound is obtained, MH⁺=592.

Example 568N¹-[(1S,2R)-3-{[(1R)-1-(3-bromophenyl)ethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE3), (1R)-1-(3-bromophenyl)ethyl]amine (VI) and “5-Me-PHTH” (IX), thetitle compound is obtained, MH⁺=645.

Example 569N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(4-fluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),3-iodobenzylamine (VI) and “5-Me-PHTH” (IX), the title compound isobtained, MH⁺=660.

Example 570N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[butyl(butyryl)amino]-5-methylbenzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and3-[butyl(butyryl)amino]-5-methylbenzoic acid (IX), the title compound isobtained, MH⁺=560.

Example 571N¹-{1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and4-methyl-N,N-dipropylisophthalic acid (IX), the title compound isobtained, MH⁺=546.

Example 572N³-{1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N¹,N¹-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and4-methyl-N,N-dipropylisophthalic acid (IX), the title compound isobtained, MH⁺=546.

Example 573N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),3-methoxybenzylamine (VI) and 4-methyl-N,N-dipropylisophthalic acid(IX), the title compound is obtained, MH⁺=582.

Example 574N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-butyl-1H-indole-6-carboxamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and1-butyl-1H-indole-6-carboxylic acid (IX), the title compound isobtained, MH⁺=500.

Example 575N¹-[(1S,2R)-3-anilino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V), aniline(VI) and “5-Me-PHTH” (IX), the title compound is obtained, MH⁺=538.

Example 5765-bromo-N¹-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),3-bromobenzylamine (VI) and 5-bromo-N,N-dipropylisophthalic acid (IX),the title compound is obtained, MH⁺=696.

Example 577N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-methylpentanamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),3-iodobenzylamine (VI) and 4-methylpentanoic acid (IX), the titlecompound is obtained, MH⁺=531.

Example 578N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-methylpentanamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),3-iodobenzylamine (VI) and CH₃—CH₂—CH(CH₃—)—CH₂—CO—OH (IX), the titlecompound is obtained, MH⁺=531.

Example 579N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-hydroxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V),3-hydroxybenzylamine (VI) and “5-Me-PHTH” (IX), the title compound isobtained, MH⁺=568.

Example 580 tert-butyl(1S)-1-(3,5-difluorobenzyl)-3-[(3-methoxybenzyl)amino]-2-oxopropylcarbamate(XI)

tert-butyl (1S)-3-bromo-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate(III, EXAMPLE 1, 1 equivalent) is dissolved in isopropanol and treatedwith 3-methoxybenzylamine (VI, 5 equivalents). The reaction is heated atreflux for 2 hours and monitored by TLC for disappearance of the ketone(III). Upon completion, the reaction is concentrated to dryness underreduced pressure and partitioned between equal parts water and ethylacetate. The organic phase is extracted, washed two additional timeswith water, then saline, then dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The crude material ispurified by column chromatography on silica gel to give the titlecompound.

Example 581 tert-butyl(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (XIII)

tert-butyl-(1S,2R)-3-azido-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate(XII, EXAMPLE 165, 1 equivalent) is dissolved in methanol and treatedwith 10% palladium on carbon under hydrogen (50 psi). The reaction isshaken at 20–25 degrees C. for 2 hours, filtered through a diatomaceousearthpad, and concentrated under reduced pressure to dryness. The crudematerial is purified by column chromatography on silica gel to give thetitle compound.

Example 582 Benzyl(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate(VII)

A mixture of benzyl (1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V,0.22 g, 0.74 mmol), 3-methoxybenzylamine (VI, 0.13 g, 0.92 mmol), andethanol (2 mL) is stirred at reflux for 2.3 hours and then cooled andconcentrated under reduced pressure. The residue is chouromatographed(silica gel; methanol/dichloromethane/ammonium hydroxide, 4/96/trace) togive the title compound, MS m/z at (m+H)⁺=435.2.

Example 583 Benzyl(1S,2R)-1-benzyl-2-hydroxy-3-(tert-butylcarbamoyl)-3-[(3-methoxybenzyl)amino]propyl-carbamate(XXXIV)

A mixture of benzyl(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl-carbamate(VII, EXAMPLE 582, 9.00 g, 21.0 mmol), di-tert-butyl dicarbonate (5.00g, 23 mmol), sodium carbonate monohydrate (3.12 g, 25 mmol), THF (200mL), and water (100 mL) is stirred at 20–25 degrees C. for 2 hours. THFis removed under reduced pressure and the residue is partitioned betweenethyl acetate and water. The organic layer is then washed with saline,dried over anhydrous sodium sulfate, filtered, and concentrated. Columnchromatography (silica gel; methanol/dichloromethane, 1/99) gives thetitle compound, NMR (300 MHz, CDCl₃)_(delta) 7.26, 6.79, 5.00, 4.42,3.89, 3.78, 3.44, 3.28, 2.91, 1.49; MS (ESI+) for C₃₁H₃₈N₂O₆ m/z(M+H)⁺=535.3.

Example 584 tert-Butyl(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)carbamate (XXXV)

A suspension of benzyl(1S,2R)-1-benzyl-2-hydroxy-3-(tert-butylcarbamoyl)-3-[(3-methoxybenzyl)amino]propyl-carbamate(XXXIV, EXAMPLE 583, 10.2 g, 18.6 mmol) and palladium on carbon (5%,1.00 g) in ethanol (100 mL) is shaken in a hydrogenation apparatus underhydrogen (50 psi) for 2 hours. Then the mixture is filtered throughdiatomaceous earth and concentrated. The concentrate ischromatographed.(silica gel; methanol/dichloromethane, 5/95) to give thetitle compound, NMR (CDCl₃) δ 1.50, 2.46, 2.92, 3.04, 3.42, 3.52, 3.72,3.82, 4.49, 6.83, 7.19 and 7.28; MS (ESI+) for C₂₃H₃₂N₂O₄ m/z(M+H)⁺=401.3.

Example 585 tert-butyl(2R,3S)-3-({3-cyano-5-[(dipropylamino)carbonyl]benzoyl}amino)-2-hydroxy4-phenylbutyl(3-methoxybenzyl)carbamate(XXVI)

To a mixture of 3-cyano-5-[(dipropylamino)carbonyl]benzoic acid(IX/XXXII, PREPARATION 7, 0.086 g, 0.314 mmol) and tert-butyl(2R,3S)3-amino-2-hydroxy4-phenylbutyl(3-methoxybenzyl)carbamate (XXXV,EXAMPLE 584, 0.126 g, 0.314 mmol) in dichloromethane (0.3 mL) is addeddiethylcyanophosphonate (0.062 g, 0.330 mmol) and triethylamine (0.032g, 0.316 mmol). The mixture is stirred at 20–25 degrees for 65 hours andthen partitioned between dichloromethane and saturated aqueous sodiumbicarbonate. The organic phase is separated and dried over sodiumsulfate and concentrated. The residue is chromatographed (silica gel, 20mL; methanol/dichloromethane, 5/95) to give several mixed fractions,which are combined and rechromatographed (silica gel; acetone/hexane,20/80) to give the title compound, MS (ESI+) for C₃₅H₄₈N₄O₆ M/z 657.6(M+H)⁺=657.6; (M+Na)=679.5 and (M—C₄H₉O₂)=557.5.

Example 586N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-cyano-N³,N³-dipropylisophthalamidehydrochloride (X)

A mixture of tert-butyl(2R,3S)-3-({3-cyano-5-[(dipropylamino)carbonyl]benzoyl}amino)-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)carbamate(XXXVI, EXAMPLE 585, 0.080 g, 0.122 mmol), dichloromethane (1 mL), andmethanol saturated with hydrochloric acid (1 mL) is stirred for 8 hours,after which time the solvents are removed under reduced pressure. A fewdrops of methanol, followed by ether, gives the title compound, MS(ESI+) for C₃₃H₄₀N₄O₄ m/z (M+H)⁺=557.5.

Example 587N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide(X)

To a mixture of 3-(aminocarbonyl)-5-[(dipropylamino)carbonyl]benzoicacid (IX, PREPARATION 6, 0.18 g, 0.616 mmol) in dry DMF (16 mL) is addedEDC (0.182 g, 0.9 mmol), HOBT (0.127 g, 0.9 mmol), triethylamine (0.062g, 0.616 mol), and(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]4-phenyl-2-butanol (VIII,EXAMPLE 175, 0.185 g, 0.616 mmol). The mixture is stirred at 20–25degrees C. for 3 days. The mixture is partitioned between water andethyl acetate. The phases are separated and the organic phase is washedthree times with water. The organic phase is dried over anhydrousmagnesium sulfate, filtered and concentrated. Column chromatography(silica gel, 75 mL; methanol/methylene chloride, 10/90) gives the titlecompound, IR (diffuse reflectance) 3306, 3301, 3270, 2962, 1676, 1667,1663, 1645, 1638, 1627, 1615, 1550,1537, 1450 and 1439 cm⁻¹;NMR(CDCl₃)δ0.645, 0.968, 1.20, 1.43, 1.67, 2.8, 2.97, 3.38, 3.47, 3.73, 3.87, 4.31,6.78, 6.91, 7.23, 7.72, 7.87, 8.22 and 8.43.

Example 588 1-tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propylcarbamate(VII)

tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate(V, EXAMPLE 3, 1.75 g, 5.8 mmole) is mixed with isopropanol (30 ml). Thereaction flask is charged with 3-iodobenzylamine (VI). The reactionmixture is heated to reflux for 45 minutes, HPLC analysis indicatescomplete disappearance of the epoxide (V). The reaction mixture isconcentrated under reduced pressure and the residue is partitionedbetween ethyl acetate (150 ml) and aqueous hydrochloric acid (3%, 35ml). The organic phase is separated and washed with aqueous hydrochloricacid (3%, 20 ml), bicarbonate, saline and dried over sodium sulfate.Concentration under reduced pressure gives the title compound, M+H=535.

Example 589 1-9H-fluoren-9-ylmethyl(2R,3S)-3-(3-t-butyloxycarbonyl)amino-4-(3,5-difluorophenyl)-2-hydroxybutyl(3′-iodobenzyl)carbamatehydrochloride (XXXIV)

1-tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propylcarbamate(VII, EXAMPLE 588, 2.5 g, 4.7 mmole) and triethylamine (0.72 ml, 5.1mmole) in THF (10 ml) are mixed. The reaction is cooled to 0 degrees andtreated with FMOC—Cl (1.2 g, 4.7 mmole) in THF (2 ml) via additionfunnel. After 15 minutes HPLC indicates complete disappearance ofstarting material. The reaction is diluted with ethyl acetate and washedwith aqueous potassium bisulfate, saturated aqueous bicarbonate, salineand dried over sodium sulfate. Concentration under reduced pressuregives crude product which is purified by flash chromatography, elutingwith ethyl acetate/hexane (20/80) followed by ethyl acetate to give thetitle compound, M+H=757.

Example 590 1-9H-fluoren-9-ylmethyl(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl(3-iodobenzyl)carbamatehydrochloride (XXXV)

1-9H-fluoren-9-ylmethyl(2R,3S)-3-(3-t-butyloxycarbonyl)amino-4-(3,5-difluorophenyl)-2-hydroxybutyl(3′-iodobenzyl)carbamatehydrochloride (XXXIV, EXAMPLE 589, 2.9 g) in hydrochloric acid/dioxane(4N, 10 ml). The mixture is stirred 1 hour then slowly poured intorapidly stirring ether (200 ml). The product is filtered and dried togive the title compound, M+H=657.

Example 591 1-9H-fluoren-9-ylmethyl(2R,3S)-4-(3,5-difluorophenyl)-2-hydroxy-3-{[5-oxo-5-(1-piperidinyl)pentanoyl]amino}butyl(3-iodobenzyl)carbamate(XXXVI)

HOBt (81 mg, 0.6 mmole) and EDC (105 mg, 0.55 mmole) are added to1-carboxy-5-piperdinylglutaramide (IX, 100 mg, 0.5 mmole) in DMF (2 ml).The acid is activated 60 minutes then treated with1-9H-fluoren-9-ylmethyl(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-hydroxybutyl(3-iodobenzyl)carbamatehydrochloride (XXXV, EXAMPLE 590, 300 mg, 0.43 mmole) and NMM (0.19 ml,1.72 mmole). The reaction is stirred 3 hours then concentrated underreduced pressure. The residue is partitioned between ethyl acetate andsaturated aqueous bicarbonate. The organic phases are washed withaqueous potassium bisulfate, saline, dried over sodium sulfate andfinally concentrated under reduced pressure to give crude product.Purification via flash chromatography with ethyl acetate/hexane (50/50)then methanol/ethyl acetate (10/90) gives the title compound, M+H=838.

Example 5921-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-oxo-5-(1-piperidinyl)pentanamidetrifluroacetate (X)

1-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-oxo-5-(1-piperidinyl)pentanamidetrifluroacetate (XXXVI, EXAMPLE 591, 240 mg, 0.29 mmole is dissolved indiethylamine (10%, 9 ml) in methylene chloride. The reaction is stirredat 20–25 degrees overnight. The next morning the reaction isconcentrated under reduced pressure and the residue is redissolved inmethylene chloride and purified by preparative reverse phase HPLC. Theappropriate fractions are pooled and concentrated under reduced pressureand partitioned between ethyl acetate and saline. The organic phase isseparated and dried over sodium sulfate and concentrated to give thetitle compound, M+H=614.

Example 5935-(Aminosulfonyl)-N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N-dipropylisophthalamide(X)

O—(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 0.0928 g, 0.244 mmol) is added to a mixtureof, 3-(aminosulfonyl)-5-[(dipropylamino)-carbonyl]benzoic acid (XXXIX,PREPARATION 13, 0.0800 g, 0.244 mmol) and(2R,3S)-3-amino-1-[(3-methoxybenzyl)-amino]-4-phenyl-2-butanol (VIII,EXAMPLE 175, 0.0732 g, 0.244 mmol) in dry DMF (3 mL). The mixture isstirred for 18 hours at 20–25 degrees, and then partitioned betweenethyl acetate and water. The organic phase is separated and washed withsaline, dried over anhydrous sodium sulfate, filtered and concentrated.The concentrate is column chouromatographed (silica gel;methanol/dichloromethane, 5/95) to give the title compound, MS (ESI+)for C₃₂H₄₂N₄O₆S m/z (M+H)⁺=611.5; HRMS (FAB) calculated for C₃₂H₄₂N₄O₆S+H₁=611.2903, found=611.2904.

Example 594N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1-pyrrolidinylsulfonyl)isophthalamide(X)

Following the general procedure of EXAMPLE 593 and making non-criticalvariations but using3-[(dipropylamino)carbonyl]-5-(1-pyrrolidinylsulfonyl)benzoic acid(XXXIX, PREPARATION 15, the title compound is obtained, ES (ESI+) forC₃₆H₄₈N₄O₆S m/z (M+H)⁺=665.6;HRMS (FAB) calculated forC₃₆H₄₈N₄O₆S+H₁=665.3372, found=665.3393.

Example 595N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylamino)sulfonyl]-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLE 593 and making non-criticalvariations but using3-[(dipropylamino)carbonyl]-5-[(methylamino)-sulfonyl]benzoic acid(XXXIX, PREPARATION 17, the title compound is obtained, MS (ESI+) forC₃₃H₄₄N₄O₆S m/z (M+H)⁺=625.5.

Example 596N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(dimethylamino)sulfonyl]-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLE 593 and making non-criticalvariations but using3-[(dimethylamino)sulfonyl]-5-[(dipropylamino)carbonyl]-benzoic acid(XXXIX, PREPARATION 19), the title compound is obtained, MS (ESI+) forC₃₄H₄₆N₄O₆S m/z (M+H)⁺=639.5.

Examples 597–619

Following the general procedure of EXAMPLEs 589 through 592 but startingwith (2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanol(VIII, EXAMPLE 175) and using the amide forming agent (IX) of Column A,the Substituted Amine (X) of Column B is obtained.

Column A MS EX Amide Forming Column B Data # Agent (IX) SubstitutedAmine (X) M + H 597 2-methyl-3- N-{(1S,2R)-1-benzyl-2- 449(methylsulfonyl) hydroxy-3-[(3- propanoic acidmethoxybenzyl)amino]propyl}- 2-methyl-3-(methylsulfonyl) propanamidehydrochloride 598 3-(methylsulfonyl) N-{(1S,2R)-1-benzyl-2- 435propanoic acid hydroxy-3-[(3-methoxybenzyl) amino]propyl}-3-(methylsulfonyl)propanamide hydrochloride 599 2-amino-1,3-thiazole-2-amino-N-{(1S,2R)-1-benzyl- 427 4-carboxylic acid 2-hydroxy-3-[(3-hydrochloride methoxybenzyl)amino]propyl}- 1,3-thiazole-4-carboxamidedihydrochloride 600 5-(methylsulfonyl) N-{(1S,2R)-1-benzyl-2- 463pentanoic acid hydroxy-3-[(3- methoxybenzyl)amino]propyl}-5-(methylsulfonyl)pentanamide hydrochloride 601 4-anilino-4-N¹-{(1S,2R)-1-benzyl-2- 476 oxobutanoic acidhydroxy-3-[(3-methoxybenzyl) amino]propyl}-N⁴- phenylsuccinamidehydrochloride 602 (2R)-4-amino-2,3,3- (3R)-N⁴-{(1S,2R)-1-benzyl-2- 442trimethyl-4- hydroxy-3-[(3- oxobutanoic acidmethoxybenzyl)amino]propyl}- 2,2,3-trimethylbutanediamide hydrochloride603 3-[(dipropylamino) N-{(1S,2R)-1-benzyl-2- 520 sulfonyl]hydroxy-3-[(3- propanoic acid methoxybenzyl)amino]propyl}-3-[(dipropylamino)sulfonyl]- propanamide hydrochloride 6045-(dipropylamino)-5- N¹-{(1S,2R)-1-benzyl-2- 498 oxopentanoic acidhydroxy-3-[(3-methoxybenzyl) amino]propyl}-N⁵,N⁵- dipropylpentanediamidehydrochloride 605 4-oxo-4-(1-piperidinyl) N-{(1S,2R)-1-benzyl-2- 468butanoic acid hydroxy-3-[(3-methoxybenzyl) amino]propyl}-4-oxo-4-(1-piperidinyl)butanamide hydrochloride 606 4-(dipropylamino)-4-N~1~-{(1S,2R)-1-benzyl-2- 484 oxobutanoic acidhydroxy-3-[(3-methoxybenzyl) amino]propyl}-N⁴,N⁴- dipropylsuccinamidehydrochloride 607 5-oxo-5-(1-piperidinyl) N-{(1S,2R)-1-benzyl-2- 482pentanoic acid hydroxy-3-[(3-methoxybenzyl) amino]propyl}-5-oxo-5-(1-piperidinyl)pentanamide hydrochloride 608 5-anilino-5-N^(1-{(1S,2R)-1-benzyl-2-) 490 oxopentanoic acidhydroxy-3-[(3-methoxybenzyl) amino]propyl}-N⁵- phenylpentanediamidehydrochloride 609 3,3-dimethyl-4-oxo-4- N-{(1S,2R)-1-benzyl-2- 496(1-piperidinyl) hydroxy-3-[(3-methoxybenzyl) butanoic acidamino]propyl}-3,3-dimethyl-4- oxo-4-(1-piperidinyl) butanamidehydrochloride 610 4-(isopentylsulfonyl) N-{(1S,2R)-1-benzyl-2- 505butanoic acid hydroxy-3-[3-methoxybenzyl) amino]propyl}-4-(isopentylsulfonyl) butanamide hydrochloride 611 4-(dipropylamino)-2,2-N¹-{(1S,2R)-1-benzyl-2- 512 dimethyl-4- hydroxy-3-[(3-methoxybenzyl)oxobutanoic acid amino]propyl}-2,2-dimethyl- N⁴,N⁴-dipropylsuccinamidehydrochloride 612 4-[(dipropylamino) N-{(1S,2R)-1-benzyl-2- 534sulfonyl] hydroxy-3-[(3-methoxybenzyl) butanoic acid amino]propyl}-4-[(dipropylamino)sulfonyl] butanamide hydrochloride 6134-[(methylanilino) N-{(1S,2R)-1-benzyl-2- 540 sulfonyl]hydroxy-3-[(3-methoxybenzyl) butanoic acid amino]propyl}-4-[(methylanilino)sulfonyl]butana- mide hydrochloride 6143-[(methylanilino) N-{(1S,2R)-1-benzyl-2- 526 sulfonyl]propanoichydroxy-3-[(3-methoxybenzyl) acid amino]propyl}-3-[(methylanilino)sulfonyl]propan- amide 615 Acetic acidN-{(1S,2R)-1-benzyl-2- 343 hydroxy-3-[(3-methoxybenzyl)amino]propyl}acetamide hydrochloride 616 3-(isopentylsulfonyl)N-{(1S,2R)-1-benzyl-2- 491 propanoic acid hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3- (isopentylsulfonyl) propanamide hydrochloride 6175-oxo-5-(1-piperidinyl) N-{(1S,2R)-1-(3,5- 614 pentanoic aciddifluorobenzyl)-2-hydroxy-3- [(3-iodobenzyl)amino]propyl}-5-oxo-5-(1-piperidinyl) pentanamide trifluoroacetate 6185-oxo-5-(1-piperidinyl) N-{(1S,2R)-1-benzyl-2- 578 pentanoic acidhydroxy-3-[(3-iodobenzyl) amino]propyl}-5-oxo-5-(1-piperidinyl)pentanamide trifluoroacetate 619 3-[(dipropylamino)N-{(1S,2R)-1-(3,5- 652 sulfonyl] difluorobenzyl)-2-hydroxy-3- propanoicacid [(3-iodobenzyl)amino]propyl}- 3-[(dipropylamino)sulfonyl]propanamide

Example 620N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-ethyl-N³,N³-dipropylisophthalamide(X)

Diethyl cyanophosphonate (0.132 mL, 0.870 mmol) is added to a mixture of3-[(dipropylamino)carbonyl]-5-ethylbenzoic acid (IX, PREPARATION 21,0.200 g, 0.720 mmol),(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanol (VIII,EXAMPLE 175, 0.216 mg, 0.720 mmol), and triethylamine (0.121 mL, 0.870mmol) in dichloromethane (3 mL). The mixture was stirred for 1 hour at20–25 degrees C. Dichloromethane is then removed under reduced pressure.The residue is partitioned between ethyl acetate and water. The organicphase is separated and is washed with saline, dried over anhydroussodium sulfate, filtered and concentrated. The concentrate is columnchouromatographed (silica gel; methanol/dichloromethane, 5/95) to givethe title compound, MS (ESI+) for C₃₄H₄₅N₃O₄ m/Z (M+H)⁺=560.4; HOURMS(FAB) calculated for C₃₄H₄₅N₃O₄+H=560.3488, found=560.3487.

Example 621N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-isobutyl-N³,N³-dipropylisophthalamide

Following the general procedure of PREPARATIONS 20 and 21 and makingnon-critical variations but using isobutylboronic acid, and followingthe general procedure of EXAMPLE 620 but using the 5-isobutylisophthalicacid (IX), the title compound is obtained, MS (ESI+) for C₃₆H₄₉N₃O₄ M/z(M+H)⁺=588.6; HRMS (FAB) calculated for C₃₆H₄₉N₃O₄+H₁=588.3801,found=588.3810.

Example 622N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-tert-butyl-N³,N³-dipropylisophthalamide

Following the general procedure of PREPARATIONS 20 and 21 and makingnon-critical variations but using tert-butylboronic acid, and followingthe general procedure of EXAMPLE 620 but using the tert-butylphthalicacid (IX), the title compound is obtained, MS (ESI+) for C₃₆H₄₉N₃O₄ m/z(M+H)⁺=588.5; HRMS (FAB) calculated for C₃₆H₄₉N₃O₄+H₁=588.3801,found=588.3791.

Example 623N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-cyano-N³-propylisophthalamide(X)

Following the general procedure of EXAMPLE 586 and making non-criticalvariations, but using tert-butyl(2R,3S)-3-({3-cyano-5-[(propylamino)carbonyl]benzoyl}amino)-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)carbamate(XXXVI) the title compound is obtained, M+H=515.1.

Examples 624–628

Following the general procedure of EXAMPLE 587 and making non-criticalvariations, but using the appropriate amines (VIII) and amide formingagents (IX), for example PREPARATIONS 6 and 19, the titled compounds areobtained.

EXAM- M + PLE Substituted Amine (X) H = 624N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3- 611.0methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5- benzenetricarboxamide625 N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3- 603.0methoxybenzyl)amino]propyl}-N³,N³-dimethyl-N⁵,N⁵-dipropyl-1,3,5-benzenetricarboxamide 626N¹-[(1S,2R)-3-amino-1-benzyl-2-hydroxypropyl]- 455.1N³,N³-dipropyl-1,3,5-benzenetricarboxamide 627N¹-[(1S,2R)-1-benzyl-2-hydroxy-3- 525.6(isopentylamino)propyl]-N³,N³-dipropyl-1,3,5- benzenetricarboxamide 628N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3- 533.1methoxybenzyl)amino]propyl}-N³-propyl-1,3,5- benzenetricarboxamide

Example 629N-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino}propyl]-3-[butyryl(propyl)amino]-5-methylbenzamide(X)

Following the procedure of EXAMPLE 570 and making non-criticalvariations, diethyl cyanophosphonate (0.0760 mL, 0.550 mmol) is added toa mixture of 3-[butyryl(propyl)amino]-5-methylbenzoic acid (IX, 0.120 g,0.460 mmol),(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanol (VIII,0.137 g, 0.460 mmol), and triethylamine (0.0760 mL, 0.550 mmol) indichloromethane (5 mL). The mixture is stirred for 1 hour at 20–25degrees C. Dichloromethane is then removed under reduced pressure. Theresidue is partitioned between ethyl acetate and water. The organic isseparated, is washed with saline, dried over anhydrous sodium sulfate,filtered and concentrated. The concentrate is column chromatographed(silica gel; methanol/dichloromethane, 5/95) to give the title compound,NMR (400 MHz, CDCl₃) δ 7.09, 4.15, 3.80, 3.79, 3.60, 3.02, 2.84, 2.36,1.94, 1.56, 1.49, 0.87 and 0.81; MS (ESI+) for C₃₃H₄₃N₃O₄ m/z(M+H)⁺=546.3; HRMS (FAB) calculated for C₃₃H₄₃N₃O₄+H=546.3331,found=546.3331.

Example 630N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-propyl-1H-indole-6-carboxamide(X)

Following the general procedure of EXAMPLE 539 and making non-criticalvariations, the title compound is obtained, IR (diffuse reflectance)3330, 3314, 2960, 2952, 2931, 2873, 1621, 1599, 1525, 1499, 1467, 1353,1283, 1253 and 786 cm⁻¹.

Example 631N-{(S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-propyl-1H-indole-6-carboxamide(-X)

Following the general procedure of EXAMPLE 539 and making non-criticalvariations, the title compound is obtained, IR (diffuse reflectance)3289, 1627, 1621, 1595, 1531, 1525, 1520, 1507, 1466, 1458, 1450, 1349,1317, 1252 and 1117 cm⁻¹.

Examples 633–708

Following the general procedures of CHART A as well as PREPARATIONs1–13, EXAMPLEs 1–13, 321–48–579, 597–622 and 624–631 and makingnon-critical variations and using the appropriate reagents, thesubstituted amines (X) of EXAMPLES 633–708 are obtained.

EXAMPLE Substituted Amine (X) MH⁺ = 633N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,4-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide580 634 N¹-[(1S,R)-3-[(3-aminobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide567 635N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}octanamide559 636 N³-[(1S,2R)-1-(3,5-difluoro- 635benzyl)-2-hydroxy-3-({1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}amino)propyl]-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide637 N¹-[(1S,2R)-1-(3,5-difluoro- 648benzyl)-2-hydroxy-3-({1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}amino)propyl]-5-methy-N³,N³-dipropylisophthalamide638 N¹-((1S,2R)-1-(3,5-difluoro- 594benzyl)-2-hydroxy-3-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide639 N¹-{(1S,2R)-1-(3,5-difluoro- 578benzyl)-3-[(1R)-3,4-dihydro-1H-inden-1-ylamino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide640N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-methylbenzamide551 641N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(1H-isoindol-3-ylamino)propyl]-5-methyl-N³,N³-dipropylisophthalamide577 642 N¹-((1S,2R)-1-(3,5-difluoro- 600benzyl)-2-hydroxy-3-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide643N¹,N¹-diallyl-5-chloro-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}isophthalamide597 644 5-chloro-N¹-{(1S,2R)-1-(3,5-difluoro- 633benzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N³,N³-bis(2-methoxyethyl)isophthalamide645 N³-{(1S,2R)-1-(3,5-difluoro- 593benzyl)-2-hydroxy-3-[(1-phenylcyclopentyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide646N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide580 647 N¹-((1S,2R)-1-(3,5-difluoro- 595benzyl)-3-{[3-(dimethylamino)benzyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide648 N¹-((1S,2R)-1-(3,5-difluoro- 570benzyl)-3-{[(4,5-dimethyl-2-furyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide649N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopentyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide606 650N¹-[(1S,2R)-3-(cyclopropylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide502 651N¹-[(1S,2R)-3-[(cycloproylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide516 652N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide630 653N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-furylmethyl)amino]-2-hydroxypropyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide529 654 N¹-{(1S,2R)-1-(3,5-difluoro- 546benzyl)-2-hydroxy-3-[(tetrahydro-2-furanylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide655 N³-{(1S,2R)-1-(3,5-difluoro- 565benzyl)-2-hydroxy-3-[(1-phenylcyclopropyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide656N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-oxo-3-azepanyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide573 657 N¹-((1S,2R)-1-(3,5-difluoro- 556benzyl)-2-hydroxy-3-{[(3-methyl-2-furyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide658 N¹-((1S,2R)-1-(3,5-difluoro- 546benzyl)-2-hydroxy-3-{[(2S)-tetrahydro-2-furanylmethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide659 5-chloro-N¹-{(1S,2R)-1-(3,5-difluoro- 593benzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N³,N³-di(2-propynyl)isophthalamide660N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropenylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide592 661N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-propoxyethyl)amino]propyl}-5-methyl-N³,³-dipropylisophthalamide548 662 N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(hexylamino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide546 663 N-{(1S,2R)-1-(3,5-difluoro- 633benzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzamide664 methyl 4-({[(2R,3S)-4-(3,5-difluoro- 610phenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)benzoate665N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide520 666N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-isoxazolylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide543 667 (1R,2R)-N¹-{(1S,2R)-1-(3,5-difluoro- 628benzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N²,N²-dipropyl-1,2-cyclopropanedicarboxamide668 N³-((1S,2R)-1-(3,5-difluoro- 533benzyl)-2-hydroxy-3-{[(2S)-tetrahydro-2-furanylmethyl]amino}propyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide669N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide582 670N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide594 6714-(butyrylamino)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}benzamide622 672N¹-[(1S,2R)-3-[(3-amino-3-oxopropyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide533 673N³-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide1-oxide 555 674N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide688 675 N¹-{(1S,2R)-1-(3,5-difluoro- 572benzyl)-2-hydroxy-3-[(7-oxabicyclo[2.2.1]hept-2-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide676N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide576 677 N¹-((1S,2R)-1-(3,5-difluoro- 573benzyl)-2-hydroxy-3-{[(2-methyl-1,3-thiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide678 N¹-((1S,2R)-1-(3,5-difluoro- 587benzyl)-3-{[(2-ethyl-1,3-thiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide679N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3R)-2-oxoazepanyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide573 680N¹-[(1S,2R)-3-(cyclobutylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide516 681N¹-[(1S,2R)-3-(butylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-ethynyl-N³,N³-dipropylisophthalamide528 682N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-ethynyl-N³,N³-dipropylisophthalamide590 683N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(5-hexynylamino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide542 684 N³-((1S,2R)-1-(3,5-difluoro- 543benzyl)-2-hydroxy-3-{[(5-methyl-2-furyl)methyl]amino}propyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide685N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide532 686 N¹-((1S,2R)-1-(3,5-difluoro- 570benzyl)-3-{[1-(2-furyl)-1-methylethyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide687 N¹-((1S,2R)-1-(3,5-difluoro- 599benzyl)-2-hydroxy-3-{[(3-isobutyl-5-isoxazolyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide688 N¹-((1S,2R)-1-(3,5-difluoro- 615benzyl)-2-hydroxy-3-{[(2-isobutyl-1,3-thiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide689N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(dipropylamino)sulfonyl]propanamide554 690N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide516 691N¹-((1S,2R)-1-benzyl-3-{[2-(2-chlorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide551 692N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(2-oxo-1-pyrrolidinyl)propyl]amino}propyl)-N³,N³-dipropylisophthalamide537 693N¹-{(1S,2R)-1-benzyl-3-{(cyclohexylmethyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide508 694N¹-[(1S,2R)-1-benzyl-3-(cyclopropylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide452 695N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-oxo-3-azepanyl)amino]propyl}-N³,N³-dipropylisophthalamide523 696N-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-3-(butylsulfonyl)benzamide531 697N¹-[(1S,2R)-1-benzyl-3-({2-[(2-ethylhexyl)oxy]ethyl}amino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide568 698 N¹-((1S,2R)-1-benzyl-2-hy- 544droxy-3-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-N³,N³-dipropylisophthalamide699N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[1-(4-hydroxyphenyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide532 700N¹-[(1S,2R)-1-benzyl-3-(cylcoheptylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide508 701N¹-{(1S,2R)-1-benzyl-3-[([1,1′-biphenyl]-2-ylmethyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide578 702N¹-{(1S,2R)-1-benzyl-3-[(2-fluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide520 703N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(dimethylamino)benzamide484 704N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-naphthamide491 705 N¹-[(1S,2R)-1-benzyl-3-({2-[({5-[(dimethyl- 609amino)methyl]-2-furyl}methyl)sulfanyl]ethyl}amino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide706N¹-[(1S,2R)-1-benzyl-3-({2-[(2-chloro-6-fluorobenzyl)sulfanyl]ethyl}amino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide615 707 N¹-[(1S,2R)-3-[([1,1′-bi- 628phenyl]-4-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide708N¹-[(1S,2R)-1-(3,5-diflorobenzyl)-2-hydroxy-3-(1-naphthylamino)propyl]-5-methyl-N³,N³-dipropylisophthalamide588

Examples 709–737

Following the general procedure of CHART D and EXAMPLEs 165–169 andmaking non-critical variations and using the appropriate reagents, thesubstituted amines (X) of EXAMPLES 709–737 are obtained.

EXAMPLE Substituted Amine (X) MH⁺ 709 N¹-{(1S,2R)-1-(3,5-difluoro- 542benzyl)-2-hydroxy-3-[(1H-imidazol-5-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide710 N¹-((1S,2R)-1-(3,5-difluoro- 618benzyl)-2-hydroxy-3-{[(2-phenyl-1H-imidazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide711 N¹-((1S,2R)-1-(3,5-difluoro- 556benzyl)-2-hydroxy-3-{[(1-methyl-1H-imidazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide712 N¹-[(1S,2R)-3-{[(2-butyl-4-chloro-1H-imi- 633dazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide713 N¹-[(1S,2R)-3-{[(6-chloro- 633imidazo[2,1-b][1,3]thiazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide714 N¹-((1S,2R)-1-(3,5-difluoro- 606benzyl)-2-hydroxy-3-{[(1-methyl-1H-benzimidazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide715 N¹-((1S,2R)-1-(3,5-difluoro- 618benzyl)-2-hydroxy-3-{[(2-hydroxy-1-naphthyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide716 N¹-((1S,2R)-1-(3,5-difluoro- 620benzyl)-2-hydroxy-3-{[(4-oxo-4H-chouromen-3-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide717 N¹-((1S,2R)-1-(3,5-difluoro- 662benzyl)-3-{[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-propylisophthalamide 718 N¹-[(1S,2R)-3-({[5-cyano-6-(methyl- 624sulfanyl)-2-pyridinyl]methyl}amino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide719 [5-({[(2R,3S)-4-(3,5-difluoro- 614phenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl-2-furyl]methylacetate 720N¹-[(1S,2R)-3-[(1-benzofuran-3-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide592 721 methyl 4-({[(2R,3S)-4-(3,5-difluoro- 613phenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)-1-methyl-1H-pyr-role-2-carboxylate 722 N¹-[(1S,2R)-1-(3,5-difluoro- 681benzyl)-2-hydroxy-3-({[1-(phenylsulfonyl)-1H-pyrrol-2-yl]methyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide723 N¹-((1S,2R)-1-(3,5-difluoro- 555benzyl)-2-hydroxy-3-{[(1-methy-1H-pyrrol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide724 N¹-[(1S,2R)-3-{[(4-chloro-1-meth- 591yl-1H-pyrazol-3-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide725 N¹-((1S,2R)-1-(3,5-difluoro- 646benzyl)-3-{[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide726 N¹-[(1S,2R)-3-{[(5-chloro-3-meth- 667yl-1-phenyl-1H-pyrazol-4-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide727 N¹((1S,2R)-1-(3,5-difluoro- 618benzyl)-2-hydroxy-3-{[(3-phenyl-1H-pyrazol-4-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide728 N¹-[(1S,2R)-3-{[(5-chloro-2-thie- 593nyl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide729 N¹-((1S,2R)-1-(3,5-difluoro- 650benzyl)-2-hydroxy-3-{[(3-phenoxy-2-thienyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide730N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-quinolinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide603 731N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-quinolinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide603 732 N¹-((1S,2R)-1-(3,5-difluoro- 605benzyl)-2-hydroxy-3-{[(1-methyl-1H-indol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide733 N¹-[(1S,2R)-3-{[(1-ben- 681zyl-1H-indol-3-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide734 N¹-((1S,2R)-1-(3,5-difluoro- 605benzyl)-2-hydroxy-3-{[(1-methyl-1H-indol-3-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide735 N¹-{(1S,2R)-1-(3,5-difluoro-benzyl)-2-hy- 745droxy-3-[({1-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl}methyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide736 N¹-[(1S,2R)-3-{[(2-butyl-1H-imi- 598dazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide737 methyl 3-({[(2R,3S)-4-(3,5-difluoro- 649phenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)-1H-indole-6-carboxylate

Example 7383-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-[butyl(butyryl)amino]benzyldiethyl phosphate (X)

Following the general procedure of CHART L and EXAMPLE 620 and makingnon-critical variations, the title compound is obtained, HRMS(FAB)=712.3749.

Example 739N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(cyanomethyl)-N³,N³-dipropylisophthalamide(X)

Step 1. A mixture of diethyl 1,3,5-benzenetricarboxylate (5.2 g) andborane methylsulfide complex (6.1 g) is stirred in THF (150 mL) at 20–25degrees C. overnight. The mixture is then treated with methanol,concentrated to dryness, and chouromatographed (silica gel) to givediethyl 5-(hydroxymethyl)isophthalate. Diethyl5-(hydroxymethyl)isophthalate (3.4 g) is hydroyzed in ethanol and waterwith lithium hydroxide monohydrate (0.57 g) at 20–25 degrees C. for 3.5hours at which time the solvents are removed under reduced pressure.Water (100 mL) is added and the mixture is acidified to pH=4 withconcentrated hydrochloric acid. The mixture is extracted with ethylacetate and dried over magnesium sulfate, filtered, and concentrated togive 3-(ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid, high resolutionMS MH+=225.0769. 3-(Ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid (2.3g), EDC (3.0 g), 1-HOBT (2.1 g), diisopropylethylamine (2.7 mL),dipropyl amine (2.8 mL), and DMF (50 mL) are stirred at 20–25 degrees C.overnight. The mixture is then partitioned between ethyl acetate, water,and saline. The organic phase is separated and dried over magnesiumsulfate, filtered, and concentrated. Chromatography (silica gel) givesethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate, NMR (CDCl₃)δ 0.77, 1.0, 1.4, 1.6, 1.7, 3.2, 3.5, 4.4, 4.8, 7.6, 8.0 and 8.1.

Step 2. A mixture of ethyl3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate (1.5 g) andphosphorous tribromide (0.95 mL) is stirred in dichloromethane (10 mL)and heated at 50 degrees C. for 4 hours and then cooled and partitionedbetween dichloromethane and water. The organic phase is separated andwashed with aqueous sodium bicarbonate and then dried over magnesiumsulfate and taken to dryness to give ethyl3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate, high resolution MSMH+=370.1020. Ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate(1.4 g) and sodium cyanide (0.2 g) are stirred in dry DMSO (25 mL) at20–25 degrees C. for 3.5 hours and the mixture is then partitionedbetween ethyl acetate, water and saline. The organic layer is separatedand dried over magnesium sulfate and taken to dryness under reducedpressure to give ethyl3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate. Ethyl3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate (0.6 g) ishydrolyzed with lithium hydroxide monohydrate (0.1 g) in ethanol andwater at 20–25 degrees C. overnight and then added to water (50 mL). ThepH is adjusted to 4 using concentrated hydrochloric acid and the mixtureis partitioned between ethyl acetate, water, and saline. The organicphase is separated and dried over magnesium sulfate and taken to drynessunder reduced pressure to give3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoic acid, MS M+H=287.2.

Step 3. A mixture of 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoicacid (IX, 0.13 g),(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanol (VIII,0.14 g), HATU (0.17 g), and dichloromethane (10 mL) is stirred at 40degrees C. overnight. After cooling, the mixture is washed with waterand the organic phase is separated and dried over magnesium sulfate andtaken to dryness under reduced pressure. Chromatography (silica gel)gives the title compound, M+H=571.2.

Example 740N1-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(hydroxymethyl)-N³,N³-dipropylisophthalamide(X)

Following the procedure of CHART P and EXAMPLE 739 and makingnon-critical variations but using3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoic acid (IX) and(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]4-phenyl-2-butanol (VIII), thetitle compound is obtained, HRMS (FAB)=615.3571.

Example 741N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide(X)

Step 1: A mixture of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate(XXI, 200 mg, 0.58 mmol), PdCl₂(Ph₃P)₂ (16 mg, 0.03 mol %) and copper(I) iodide (6 mg, 0.05 mol %/o) in triethylamine (1.2 mL) is heated toreflux. (Trimethylsilyl) acetylene (100 microliter, 0.7 mmol) is added,and the mixture stirred for 3 hours, cooled to 20–25 degrees, dilutedwith water (20 mL), and extracted with chloroform (3×15 mL). Thecombined organic extracts are washed with saline (20 mL), dried oversodium sulfate and concentrated under reduced pressure to give methyl3-[(dipropylamino)carbonyl]-5-ethynylbenzoate (XXXII, 185.5 mg), NMR(300 MHz, CDCl₃): δ 7.95, 7.75, 7.43, 3.74, 3.25, 2.95, 1.49, 1.34,0.79, 0.56 and 0.06.

Step 2: To a stirred mixture of the protected methyl3-[(dipropylamino)carbonyl]-5-ethynylbenzoate (XXXII, Step 1, 185.3 mg,0.49 mmol) in methanol (2.5 mL) is added a mixture of potassiumhydroxide (2.9 mL of a 1 M mixture in water, 2.9 mmol). The reactionmixture is stirred for 4 hours diluted with chloroform (40 mL), thephases are separated and the organic phase is concentrated under reducedpressure to give 3-[(dipropylamino)carbonyl]-5-ethynylbenzoic acid, NMR(300 MHz, CDCl₃): δ 8.22, 8.05, 7.71, 3.48, 3.17, 3.16, 1.71, 1.55, 1.00and 0.78.

Step 3: To a stirred mixture of3-[(dipropylamino)carbonyl]-5-ethynylbenzoic acid (70 mg, 0.24 mmol) inDMF (2.5 mL) is added(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanoldihydrochloride (VIII, 81 mg, 0.24 mmol), HOBt (36 mg, 0.26 mmol) anddiisopropylethylamine (170 microliter, 0.96 mmol). To this reactionmixture is added EDC (51 mg, 0.26 mmol) and the reaction mixture isstirred overnight. The reaction mixture is diluted with ethyl acetate(30 mL), washed with water (3×50 mL), hydrochloric acid (1 N, 30 mL),saturated sodium bicarbonate (30 mL), saline (30 mL), dried over sodiumsulfate and concentrated under reduced pressure. Purification by flashchromatography (silica, ethyl acetate to methanol/chloroform, 1/10)gives the title compound, IR (KBr): 3276, 2956, 2921, 1610, 1450 and1264 cm⁻¹; ESI-MS (m/z) [M+H]⁺=556.

Example 742N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³,N³-dipropyl-5-prop-1-ynylisophthalamide(X)

Following the general procedure of EXAMPLE 741 and making non-criticalvariations but using propyne in place of (trimethylsilyl) acetylene andusing (2R,3S)-3-amino-1-[(3-iodobenzyl)amino]4-phenyl-2-butanoldihydrochloride (VIII) in place of(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]4-phenyl-2-butanoldihydrochloride (VIIIH), the title compound is obtained, IR (ATR): 3305,2930, 2872, 1613 and 1537 cm⁻¹; ESI-MS (m/z) [M+H]⁺=666.

Example 743N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-ethynyl-N³,N³-dipropylisophthalamide(X)

Step 1: A mixture of tert-butyl(1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V, 2.3 g, 8.7 mmol) and3-(trifluoromethyl)benzylamine (VI, 1.9 mL, 13.1 mmol) in 2-propanol (70mL) is heated at reflux for 4 hours. The reaction mixture is cooled to20–25 degrees and concentrated under reduced pressure to give tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propylcarbamate(VII, 3.1 g) as a solid, ESI-MS (m/z) [M+H]⁺=439.

Step 2: A mixture of tert-butyl(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propylcarbamate(VII, step 1, 2.5 g, 5.7 mmol) and hydrochloric acid (29 mL of a 4.0 Mmixture in dioxane, 114 mmol) is stirred at 20–25 degrees. A precipitateforms and is collected by filtration, washed with ether, and dried underreduced pressure to give(2R,3S)-3-amino-4-phenyl-1-{[3-(trifluoromethyl)benzyl]amino}-2-butanoldihydrochloride (VIII, 2.13 g), ESI-MS (m/z) [M+]⁺=339.

Step 3: A mixture of 3-[(dipropylamino)carbonyl]-5-ethynylbenzoic acid(IX, 231 mg, 0.8 mmol),(2R,3S)-3-amino-4-phenyl-1-{[3-(trifluoromethyl)benzyl]amino}-2-butanoldihydrochloride (VIII, Step 2,493.5 mg, 1.2 mmol) HOBt (162 mg, 1.2mmol), and diisopropylethylamine (832 Micro Liter, 4.8 mmol) is stirredin methylene chloride (4 mL) for 15 minutes EDC (206 mg, 1.2 mmol) isadded and the reaction mixture is stirred overnight. The reactionmixture is diluted with water, and extracted with methylene chloride(3×25 mL). The organic phase is washed with hydrochloric acid (1N, 25mL), saturated sodium bicarbonate (25 mL), saline dried over sodiumsulfate and concentrated under reduced pressure. Purification by flashcolumn chromatography (silica, 100% ethyl acetate tomethanol/chloroform, 1/9) gives title compound, IR (ATR): 3302, 2963,2932 and 1615 cm⁻¹; MS (m/z) [M+H]⁺=549.

Example 744N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLE 744 and making non-criticalvariations but using 3-iodobenzylamine hydrochloride salt (VI), thetitle compound is obtained, IR (ATR) 3295, 2960, 2927 and 1616 cm⁻¹,APCI-MS (m/z) [M+H]⁼652.

Example 745N¹-{(1S,2R)-1-benzyl-3-[(3-fluorobenzyl)amino]-2-hydroxypropyl}-5-ethynyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLE 744 and making non-criticalvariations but using 3-fluorobenzylamine (VI), the title compound isobtained, IR (ATR): 3217, 2961, 2918 and 1615 cm⁻¹; APCI-MS (m/z)[M+H]⁺=544.

Example 746N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(8-quinolinyl)isophthalamide(X)

Step 1: A mixture of methyl-3-bromo-5-[(dipropylamino)carbonyl]benzoate(XLVIII, 200 mg, 0.58 mmol), 8-quinolineboronic acid (200.6 mg, 1.2mmol), sodium carbonate (870 Micro Liter of a 2 M mixture in water, 1.74mmol) in toluene (6 mL) is degassed under reduced pressure for 15minutes and purged with argon. Palladium tetrakis(triphenylphosphine)(139 mg, 0.12 mmol) is added and the reaction mixture is degassed underreduced pressure for 15 minutes and purged with argon. The reactionmixture is heated at reflux overnight, cooled to 20–25 degrees C. anddiluted with chloroform. The organic phase is separated and washed withwater (3×50 mL), and saline, dried over sodium sulfate and concentratedunder reduced pressure. Purification by flash column chromatography(silica, ethyl acetate/hexanes, 1.3/1) gives methyl3-[(dipropylamino)carbonyl]-5-(8-quinolinyl)benzoate (XLIX, 176 mg), NMR(300 MHz, CDCl₃): delta 8.91, 8.42, 8.21, 8.09, 7.95, 7.86, 7.77, 7.64,3.94, 3.49, 3.34, 1.64, 0.99 and 0.84.

Step 2: To a mixture of methyl3-[(dipropylamino)carbonyl]-5-(8-quinolinyl)benzoate (XLIX step 1, 175.5mg, 0.45 mmol) in methanol (2 mL) is added lithium hydroxide (32.3 mg,1.4 mmol) and water (500 microliter). After stirring overnight, thereaction mixture is partitioned between ethyl acetate (10 mL) and water(10 mL). The aqueous phase is separated and acidified with hydrochloricacid (1N), and extracted with chloroform (3×40 mL). The organic phase iswashed with saline, dried (sodium sulfate) and concentrated underreduced pressure to give3-[(dipropylamino)carbonyl]-5-(8-quinolinyl)benzoic acid (IX–L, 130 mg),NMR (300 MHz, CD₃OD) δ 6 8.84, 8.39, 8.35, 8.05, 7.96, 7.90, 7.87, 7.79,7.68, 3.50, 3.37, 1.76–1.61, 0.99 and 0.84.

Step 3: A mixture of 3-[(dipropylamino)carbonyl]-5-(8-quinolinyl)benzoicacid (IX–L, Step 2,130 mg, 0.35 mmol),(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanoldihydrochloride (VIII, 117 mg, 0.35 mmol), HOBt (70 mg, 0.52 mmol) anddiisopropylethylamine (241 microliter, 1.4 mmol) in methylene chloride(2 mL) is stirred for 15 minutes EDC (89 mg, 0.52 mmol) is added and thereaction mixture is stirred overnight. The reaction mixture is dilutedwith water and extracted with methylene chloride (3×25 mL). The organicphase is washed with hydrochloric acid (1N, 25 mL), saturated sodiumbicarbonate (25 mL), saline, dried (sodium sulfate), and concentratedunder reduced pressure. Purification by flash column chromatography(silica; methanol/chloroform, 1/9) gives the title compound, IR (NaCl):3301, 2916, 2365 and 1613 cm⁻¹; APCI-MS (m/z) [M+H]⁺=659.

Example 747N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4′-methoxy-N⁵,N⁵-dipropyl[1,1′-biphenyl]-3,5-dicarboxamidehydrochloride (X)

Step 1: A mixture of 4-methoxyphenyl boronic acid (463 mg, 3.05 mmol),3-bromo-5-[(dipropylamino)carbonyl]benzoic acid (XLVIII, 1.02 g, 3.05mmol), and potassium phosphate (1.29 g, 6.10 mmol) in1,2-dimethoxyethane (10 mL) and water (5 mL) is degassed with argon for15 minutes Bis(triphenylphosphine)palladium (II) chloride (21 mg, 0.03mmol) is added, the reaction mixture is degassed again with argon, andheated at 85 degrees C. overnight. The reaction mixture is cooled to20–25 degrees C., and passed through a plug of diatomaceous earth.

The filtrate is acidified to pH=4 with hydrochloric acid (IN) andextracted with ethyl acetate. The organic phase is washed with water andsaline and dried (magnesium sulfate). The product is purified by flashcolumn chromatography (silica gel; ethyl acetate/acetic acid, 99/1) togive 5-[(dipropylamino)carbonyl]-4′-methoxy[1,1′-biphenyl]-3-carboxylicacid (IX–L, 667 mg), ESI-MS (m/z) [M+H]⁺=356.

Step 2: A mixture of5-[(dipropylamino)carbonyl]-4′-methoxy[1,1′-biphenyl]-3-carboxylic acid(IX–L, step 1, 316 mg, 0.89 mmol),(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanoldihydrochloride (VIII, 332 mg, 0.89 mmol), HOBt (181 mg, 1.34 mmol), andN-methylmorpholine (0.37 g, 3.56 mmol) in methylene chloride (8 mL) anddimethylformamide (2 mL) is stirred at 20–25 degrees for 15 minutes EDC(257 mg, 1.34 mmol) is added and the reaction mixture is stirred for 4.5hours. The reaction mixture is partitioned between methylene chlorideand water. The organic phase is washed with hydrochloric acid (1N),water, and saline, dried (magnesium sulfate), and concentrated. Theconcentrate is dissolved in a minimum of methanol, treated withhydrochloric acid (3 mL of a 1.0 M mixture in ether, 3 mmol), andstirred for 10 minutes. More ether is added to precipitate the rest ofthe product. The precipitate is collected by filtration and dried in thevacuum oven at 50 degrees C. to give the title compound, mp=205–209degrees C.; IR (ATR): 2964 and 1649 cm⁻¹; APCI-MS (m/z) [M+H]⁺=638.

Example 748N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropyl[1,1′-biphenyl]-3,5-dicarboxamidehydrochloride (X)

Step 1: A mixture of tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, 500 mg,1.67 mmol) and 3-methoxybenzylamine (VI, 0.34g, 2.51 mmol) in 2-propanol(3 mL) is heated at reflux overnight, allowed to cool to 20–25 degreesC., and concentrated under reduced pressure. The residue is crystallizedfrom ethyl acetate/hexanes and collected by filtration to affordtert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate(VII, 575 mg) as a solid: ESI-MS (m/z): 437 [M+H]⁺.

Step 2: A mixture of tert-butyl(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate(VII, Step 1, 535 mg, 1.23 mmol) in methanol (2 mL) is treated withhydrochloric acid (3.2 mL of a 1.0 M mixture in ether, 3.2 mmol), andstirred at 20–25 degrees C. for 30 minutes Ether is added until aprecipitate formed. The precipitate is collected by filtration is(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanoldihydrochloride (VIII).

Step 3: A mixture of5-[(dipropylamino)carbonyl][1,1′-biphenyl]-3-carboxylic acid (IX, 188mg, 0.56 mmol),(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanoldihydrochloride (VIII, Step 2, 230 mg, 0.56 mmol), HOBt (114 mg, 0.84mmol), and N-methylmorpholine (0.23 g, 2.24 mmol) in methylene chloride(6 mL) and dimethylformamide (1 mL) is stirred at 20–25 degrees C. for15 minutes EDC (161 mg, 0.84 mmol) is added and the reaction mixture isstirred at 20–25 degrees C. overnight. The reaction mixture is washedwith water, 1N hydrochloric acid, water, and saline, dried (sodiumsulfate), and concentrated under reduced pressure to give the titlecompound, mp 230–233degrees C.; IR (ATR): 2965, 1651, 1596 and 1267 cm¹;ESI-MS (m/z) [M+H]⁺=644.

Example 749N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropyl[1,1′-biphenyl]-3,5-dicarboxamidehydrochloride (X)

Following the general procedure of EXAMPLE 748 and making non-criticalvariations but using(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanoldihydrochloride (VIII) in place of(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanoldihydrochloride (VIII), the title compound is obtained, mp=214–219degrees C.; IR (KBr): 3227, 2961, 1632 and 1605 cm¹; ESI-MS (m/z)[M+H]⁺=608.

Example 750N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4′-[(dimethylamino)sulfonyl]-N⁵,N⁵-dipropyl-1,1′-biphenyl-3,5-dicarboxamide(X)

Step 1: A flask is charged with1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium 1:1 complex (37mg, 0.05 mmol), potassium acetate (492 mg, 4.5 mmol) andbis(pinacolato)diboron (408 mg, 1.6 mmol) and is degassed under reducedpressure for 15 min and purged with argon. To this mixture is added amixture of methyl-3-bromo-5-[(dipropylamino)carbonyl]benzoate (XXI, 500mg, 1.5 mmol) in anhydrous dimethyl sulfoxide (9 mL) and the reactionmixture is stirred at 80 degrees C for 4 hours. The reaction mixture iscooled to 20–25 degrees C., diluted with toluene (50 mL), washed withwater (3×150 mL), saline, dried (magnesium sulfate), and concentratedunder reduced pressure to give methyl3-[(dipropylamino)carbonyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate,ESI-MS (m/z) [M+H]⁺=390.

Step 2: A mixture of methyl3-[(dipropylamino)carbonyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(Step 1, 534 mg, 1.4 mmol), 4-bromobenzenedimethyl-sulfonamide (363 mg,1.4 mmol), and sodium carbonate (2 mL of a 2 M mixture in water, 4.1mmol) in toluene (10 mL) is degassed under reduced pressure for 15minutes and then purged with argon. Palladiumtetrakis(triphenylphosphine) (40 mg, 0.025 mmol) is added and thereaction mixture is degassed under reduced pressure for 15 minutes andthen purged with argon. The reaction mixture is heated at reflux for 4hours, cooled to 20–25 degrees C., filtered through a plug ofdiatomaceous earth and sodium sulfate, and the filtrate is concentratedunder reduced pressure. Purification by flash column chromatography(silica; ethyl acetate/hexanes, 1/1) gives methyl4′-[(dimethylamino)sulfonyl]-5-[(dipropylamino)carbonyl][1,1′-biphenyl]-3-carboxylate(XXXVIII), ESI-MS (m/z) [M+H]⁺=447.

Step 3: A mixture of methyl4′-[(dimethylamino)sulfonyl]-5-[(dipropylamino)carbonyl][1,1′-biphenyl]-3-carboxylate(XXXVIII, step 2, 555 mg, 1.24 mmol) in methanol (6 mL) and sodiumhydroxide (2 mL of a 6.0 M mixture in water, 12 mmol) is stirred at20–25 degrees C. for 4 hours. The reaction mixture is partitionedbetween ethyl acetate (40 mL) and water (40 mL). The aqueous phase isacidified to pH=4 with hydrochloric acid (1N), extracted with ether(3×100 mL), and the combined organic phases are concentrated underreduced pressure to give methyl4′-[(dimethylamino)sulfonyl]-5-[(dipropylamino)carbonyl][1,1′-biphenyl]-3-carboxylicacid (IX–XXXIX), NMR (300 MHz, CDCl₃): δ 8.37, 8.12, 7.89, 7.80, 3.51,3.22, 2.76, 1.74, 1.59, 1.02 and 0.79.

Step 4: A mixture of the acid (IX–XXXIX, Step 3, 150 mg, 0.35 mmol),(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanoldihydrochloride (VIII, 129 mg, 0.35 mmol) HOBt (47 mg, 0.35 mmol), andN-methylmorpholine (122 μL, 1.1 mmol) is stirred in methylene chloride(4 mL) for 15 minutes EDC (107 mg, 0.62 mmol) is added and the reactionmixture is stirred overnight. The reaction mixture is diluted withwater, and extracted with methylene chloride (3×25 mL). The organicphase is washed with hydrochloric acid (1N, 25 mL), saturated sodiumbicarbonate (25 mL), saline, dried (sodium sulfate), and concentratedunder reduced pressure. Purification by flash column chromatography(silica; 100% ethyl acetate to methanol/chloroform, 1/9) gives the titlecompound, IR (ATR): 2932, 2837 and 1593 cm⁻¹; APCI-MS (m/z) [M+H]⁺=715.

Example 751N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino}propyl]4′-[(dimethylamino)sulfonyl]-N⁵,N⁵-dipropyl-1,1′-biphenyl-3,5-dicarboxamide(X)

Following the general procedure of EXAMPLE 750 and making non-criticalvariations but using2R,3S)-3-amino-1-[(3-iodobenzyl)amino]4-phenyl-2-butanol dihydrochloride(VIII), the title compound is obtained, IR (ATR): 3303, 2930, 2872 and1614 cm⁻¹; APCI-MS (m/z) [M+H]⁺=811.

Example 752N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(3-thienyl)isophthalamidehydrochloride (X)

Step 1: To an ice-cold mixture of methyl3-amino-5-[(dipropylamino)carbonyl]benzoate (XLVIII, 1.0 g, 3.60 mmol)in aqueous hydrogen tetrafluoroborate (48% wt. in H₂O, 12.9 mmol) isadded a cold mixture of aqueous sodium nitrite (0.25 g, 3.60 mmol)dropwise. The mixture is stirred for 10 min and then extracted withethyl acetate. The organic phase is washed with water, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure togive a diazonium salt which is used without further purification, NMR(500 MHz, CD₃OD): δ 9.26, 8.86, 8.71, 4.03, 3.50, 3.22, 1.75, 1.60, 1.01and 0.79.

Step 2: To a mixture of thiophene-3-boronic acid (1.0 g, 7.82 mmol) inmethanol is added a concentrated aqueous mixture of potassium hydrogendifluoride (2.01 g, 25.8 mmol) dropwise. The reaction mixture is stirredfor 10 minutes and concentrated under reduced pressure. The resultingsolid is extracted with acetone and concentrated under reduced pressuregives crude material, which is recrystallized from acetone/ether to givepotassium trifluoro(3-thienyl)borate salt, ESI-MS (m/z) [M+H]⁺=151.

Step 3: A mixture of potassium trifluoro(3-thienyl)borate salt (step 2,0.69 g, 1.82 mmol), diazonium salt from (XLVIII, step 1, 0.42 g, 2.19mmol), and lead acetate (0.02 g, 0.09 mmol) in the dark is purged withargon for 15 minutes. Dioxane (8 mL) is added and the reaction mixtureis degassed with argon and stirred at 20–25 degrees C. overnight. Thereaction mixture is diluted with ether, washed with saline, dried overmagnesium sulfate and concentrated under reduced pressure to give methyl3-[(dipropylamino)carbonyl]-5-(3-thienyl)benzoate (XLIX) which ispurified by flash chromatography (silica; ethyl acetate/hexanes, 1/1),ESI-MS (m/z) [M+H]⁺=346.

Step 4: A mixture of methyl3-[(dipropylamino)carbonyl]-5-(3-thienyl)benzoate (XLIX, step 3, 0.31 g,0.88 mmol) in THF/methanol/sodium hydroxide (3/1/1, 5 mL) is stirred at40 degrees C. for 2 hours. The reaction is cooled to 20–25 degrees C.,diluted with water and extracted with ethyl acetate. The aqueous phaseis acidified to pH=4 and extracted with ethyl acetate. The organic phaseis washed with water and saline, dried over magnesium sulfate andconcentrated under reduced pressure to give3-[(dipropylamino)carbonyl]-5-(3-thienyl)benzoic acid (IX–L), ESI-MS(m/z) [M+H]⁺=332.

Step 5: A mixture of 3-[(dipropylamino)carbonyl]-5-(3-thienyl)benzoicacid (IX–L, step 4, 0.26 g, 0.79 mmol),(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanoldihydrochloride (VIII, 0.26 g, 0.71 mmol), HOBt (0.16 g, 1.18 mmol), andtriethylamine (0.44 mL, 3.15 mmol) in DMF (4 mL) is stirred at 20–25degrees C. for 10 minutes EDC (0.23 g, 1.18 mmol) is added and thereaction mixture is stirred for 4 hours. The reaction mixture is dilutedwith water and extracted with ethyl acetate. The organic phase is washedwith hydrochloric acid (1 N), water, and saline, dried over magnesiumsulfate and concentrated under reduced pressure. Recrystallization(methylene chloride/hexanes, 1/1) gives the title compound, mp=199–201degrees C.; IR (KBr): 3278, 2961, 2874 and 2837 cm⁻¹; ESI-MS (m/z)[M+H]⁺=614.

Example 753N-{(1R,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-pentanoylbenzamide(X)

Step 1: To an ice-cold, stirred mixture of oxalyl chloride (733 mg, 5.77mmol) in methylene chloride (5 mL) is added 3 drops ofdimethylformamide. After 10 minutes 3-(methoxycarbonyl)-5-methylbenzoicacid (LXXIII, 560 mg, 2.89 mmol) is added. The reaction mixture isstirred for 1 hour and concentrated under reduced pressure to provide anacid chloride (LXXIV), which is used without further purification.

Step 2: To a −78 degrees C., stirred mixture of acid halide (LXXIV, step1, 612 mg, 2.89 mmol) and copper (I) bromide (415 mg, 2.89 mmol) intetrahydrofuran (5 mL) is added butyl magnesium chloride (1.44 mL of a2.0 M mixture in tetrahydrofuran, 2.89 mmol). The reaction mixture iswarmed to 20–25 degrees C., quenched by addition of saturated ammoniumchloride, and diluted with ether. The organic phase is separated, washedwith saline, dried (sodium sulfate), filtered, and concentrated underreduced pressure. Purification by flash column chromatography (silica;hexanes/ethyl acetate, 6.5/1) gives methyl 3-methyl-5-pentanoylbenzoate(LXXVI), NMR (300 MHz, CD₃OD): δ 8.43, 8.05, 3.96, 3.01, 1.77, 1.55 and1.22.

Step 3: A mixture of methyl 3-methyl-5-pentanoylbenzoate (LXXVI, step 2.133 mg, 0.605 mmol) in methanol (1 mL) is stirred withtetrahydrofuran/methanol/sodium hydroxide (2 N) (3/1/1, 3 mL) for 3days. The reaction mixture is diluted with ethyl acetate and washed withwater. The aqueous phase is separated and acidified with hydrochloricacid (1 N) and extracted with methylene chloride. The organic phase isdried (sodium sulfate), filtered, and concentrated under reducedpressure to give 3-methyl-5-pentanoylbenzoic acid (IX–LXXVII), NMR (300MHz, CD₃OD): δ 8.44, 8.03, 3.10, 2.33, 1.78, 1.64 and 1.34.

Step 4: To a mixture of 3-methyl-5-pentanoylbenzoic acid (IX–LXXVII, 112mg, 0.589 mmol),(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanoldihydrochloride (VIII, 239 mg, 0.589 mmol), HOBt (80 mg, 0.589 mmol),and N-methylmorpholine (250 mg, 2.47 mmol) in methylene chloride (3 mL)is added EDC (203 mg, 1.06 mmol). The reaction mixture is stirredovernight and then partitioned between ethyl acetate and water. Theorganic phase is washed with hydrochloric acid (1 N), saturated sodiumbicarbonate, saline, dried (sodium sulfate), filtered, and concentratedunder reduced pressure. Purification by flash column chromatography(silica; methylene chloride/methanol, 12/1) gives the title compound, IR(ATR): 3297,2957, 1687 and 1628 cm⁻¹; APCI-MS (m/z) [M+H]⁺=539.

Example 754N¹-(4-hydroxybutyl)-N³-{(1S)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N¹-propylisophthalamide(X)

Step 1: To a mixture of methyl(2S)-3-[4-(benzyloxy)phenyl]-2-(tert-butoxycarbonyl)aminopropanoate(1.79 g, 4.65 mmol) in a THF/methanol/water (1/2/1, 16 ml) is addedlithium hydroxide (340 mg, 13.9 mmol) and the mixture stirred at 20–25degrees C. for 12 hours. The mixture is quenched with citric acid (10%).The resulting mixture is extracted with ethyl acetate (3×15 ml). Thecombined organic extracts are washed three times with water, dried oversodium sulfate, filtered, and concentrated under reduced pressure togive(2S)-3-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]propanoicacid which is carried on without purification. To a −78 degrees C.,stirred mixture of(2S)-3-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]propanoicacid (10.0 g, 27.0 mmol) in THF (200 mL) is added NMM (3.20 mL, 29.0mmol) and isobutyl chloroformate (3.8 mL, 29.0 mmol). The cold bath isremoved, the reaction mixture is stirred for 1 hour, and then filtered.The filtrate is kept cold and used in the next step. To an ice-cold,stirred mixture of ether (110 mL) and potassium hydroxide (40%, 35 mL)is slowly added 1-methyl-3-nitro-1-nitrosoguanidine (8.40 g, 57.0 mmol).The reaction mixture is stirred until gas evolution ends. The organicphase is separated and slowly added to an ice-cold, stirred mixture ofthe mixed anhydride filtrate from step 2. After the reaction mixture isstirred for 1 hour, nitrogen is bubbled into the mixture for 10 minutesThe resulting mixture is concentrated under reduced pressure, dilutedwith ethyl acetate (200 mL), and washed with water (100 mL). The organicphase is washed with saturated sodium bicarbonate and saline, dried oversodium sulfate, filtered, and concentrated under reduced pressure togive the diazoketone, which is carried on without purification orcharacterization. To an ice-cold, stirred mixture of diazoketone inether (100 mL) is added hydrobromous acid (48%, 4 mL, 73 mmol). The coldbath is removed, the reaction mixture stirred for 30 minutes, andpartitioned between ether and water. The organic phase separated andwashed with saturated sodium bicarbonate and saline, dried over sodiumsulfate, filtered, and concentrated under reduced pressure to givetert-butyl (1S)-1-[4-(benzyloxy)benzyl]-3-bromo-2-oxopropylcarbamate(IV) which is used without further purification or characterization. Toa −78 degrees C., stirred mixture of tert-butyl(1S)-1-[4-(benzyloxy)benzyl]-3-bromo-2-oxopropylcarbamate (IV) in aisopropanol/THF (2/1, 150 mL) is slowly added sodium borohydride (1.15g, 30.0 mmol). The reaction mixture is stirred for 30 minutes followedby the addition of water (30 mL). The resulting mixture is warmed to20–25 degrees C. and concentrated under reduced pressure in a water bathnot exceeding 30 degrees C. The crude residue is dissolved in ethylacetate and washed with water and saline. The organic phase is driedover magnesium sulfate, filtered and concentrated under reduced pressureto give the bromohydrin as a solid. To an ice-cold, stirred mixture ofbromohydrin in ethanol (150 mL) and ethyl acetate (100 ml) is added apotassium hydroxyde (1 N) ethanol mixture (36 mL, 36 mmol). The coldbath is removed and the reaction mixture is stirred for 30 minutes. Theresulting mixture is partitioned between ethyl acetate and water. Theorganic phase is separated and washed with saline, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Purificationby flash chromatography (silica; hexanes/ethyl acetate, 5/1) givestert-butyl (1S)-2-[4-(benzyloxy)phenyl]-1-[(2S)-oxiranyl]ethylcarbamate(V, as a 8/1 mixture of diastereomers), NMR (500 MHz, CDCl₃) δ7.44–7.32, 7.14, 6.93, 5.07, 4.45, 3.61, 3.00–2.60 and 1.39.

Step 2: A mixture of 4-benzyloxybutyric acid (2.69 g, 13.8 mmol),propylamine (0.82 g, 13.8 mmol), HOBt (2.05 g, 15.2 mmol),N-methylmorpholine (1.68 g, 16.6 mmol) and EDC (2.91 g, 15.2 mmol) inDMF (6 mL) is stirred at 20–25 degrees C. for 18 hours. The mixture isdiluted with ethyl acetate (40 mL) and washed with water (10 mL),hydrochloric acid (1 N, 10 mL), saturated sodium bicarbonate (10 mL),and saline (10 mL). The organic phase is separated, dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to provide4-(benzyloxy)-N-propylbutanamide (2.59 g), APCI-MS (m/z) [M+H]⁺=236.

Step 3: To an ice-cold, stirred mixture of4-(benzyloxy)-N-propylbutanamide (2.59 g, 11.0 mmol) in THF (8 mL) isadded lithium aluminum hydride (0.54 g, 14.3 mmol). The reaction mixtureis heated to 40–50 degrees C. for 5 hours. The cooled reaction mixtureis quenched with water (0.5 mL), sodium hydroxide (2 N, 1.0 mL), andsaline (0.5 mL) then diluted with ether (30 mL). The precipitate thatformed is filtered off, and the ether phase dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to giveN-[4-(benzyloxy)butyl]-N-propylamine (2.41 g), APCI-MS (m/z): 222[M+H]⁺.

Step 4: A mixture of N-[4-(benzyloxy)butyl]-N-propylamine (2.31 g, 10.44mmol), 3-(ethoxycarbonyl)-5-methylbenzoic acid (2.18 g, 10.44 mmol),HOBt (1.56 g, 11.49 mmol), N-methylmorpholine (1.37 mL, 12.52 mmol), andEDC (2.20 g, 11.49 mmol) in DMF (12 mL) is stirred at 20–25 degrees C.for 18 hours. The reaction mixture is diluted with ethyl acetate (80 mL)and washed with water (2×20 mL), hydrochloric acid (1 N, 20 mL),saturated sodium bicarbonate (20 mL) and saline (20 mL), dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.Purification by flash chromatography (silica; hexanes/ethyl acetate,1/1)gives ethyl3-{[[4-(benzyloxy)butyl](propyl)amino]carbonyl}-5-methylbenzoate (1.79g), NMR (500 MHz, DMSO-d₆): _(delta)7.80, 7.64, 7.40, 7.38–7.16,4.50–4.43, 4.34–4.29, 3.53–3.30, 3.20–3.06, 2.41–2.36, 1.70–1.40,1.36–1.29, 0.94–0.84 and 0.82–0.72; APCI-MS (m/z) [M+H]⁺=412.

Step 5: To a mixture of ethyl3-{[[4-(benzyloxy)butyl](propyl)-amino]carbonyl}-5-methylbenzoate (1.75g, 4.25 mmol) in THF/ethanol/water (1/2/1, 30 mL) is added lithiumhydroxide (0.31 g, 12.76 mmol). The reaction mixture is stirred for 2 hand then acidified to pH=3 with concentrated hydrochloric acid (0.5 mL).The reaction mixture is extracted with ethyl acetate (2×30 mL), driedover magnesium sulfate, filtered, and concentrated under reducedpressure to give3-{[[4-(benzyloxy)butyl](propyl)amino]carbonyl}-5-methylbenzoic acid(IX, 1.63 g), ESI-MS (m/z) [M+H]⁺=384.

Step 6: A mixture of tert-butyl(1S)-2-[4-(benzyloxy)phenyl]-1-[(2S)-oxiranyl]ethylcarbamate (V, 1.58 g,4.28 mmol) and 3-methoxybenzylamine (VI, 825 microliter, 6.42 mmol) inisopropanol (45 mL) is heated to 90 degrees C. for 4 hours. Upon coolingto 20–25 degrees C., the reaction mixture is concentrated under reducedpressure. Purification by flash chromatography (silica; methylenechloride/methanol/ammonium hydroxide 98/1/1 to 95/:4/1) gives tert-butyl(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate(VII, 1.97 g), NMR (300 MHz, MeOH-d₄): δ 7.41–6.79, 5.05, 4.33–3.33,3.74, 3.54, 3.03–2.46 and 1.29; ESI-MS (m/z) [M+H]⁺=507.

Step 7: tert-Butyl(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propylcarbamate(VII, step 6, 2.34 g, 4.62 mmol) in dioxane (10 mL) is treated withhydrochloric acid (12 mL of a 4.0 M mixture in dioxane, 48 mmol) for 2hours. The precipitate that forms is collected by filtration, washedwith ether, and dried under reduced pressure overnight to give(2R,3S)-3-amino-4-[4-(benzyloxy)phenyl]-1-[(3-methoxybenzyl)amino]-2-butanolhydrochloride (VIII), NMR (300 MHz, MeOH-d₄): δ 7.44–6.96, 5.05, 4.21,3.83, 3.65) and 3.21–2.77; ESI-MS (m/z) [M+H]⁺=407.

Step 8: To an ice-cold, stirred mixture of3-{[[4-(benzyloxy)butyl](propyl)amino]carbonyl}-5-methylbenzoic acid(IX, 310 mg, 0.809 mmol),(2R,3S)-3-amino-4-[4-(benzyloxy)phenyl]-1-[(3-methoxybenzyl)amino]-2-butanolhydrochloride (VIII, 359 mg, 0.809 mmol), andbromotripyrrolidinophosphonium hexafluorophosphate (415 mg, 0.890 mmol)in methylene chloride (10 mL) is added diisopropylethylamine (285microL, 1.62 mmol) dropwise. The resulting mixture is stirred at 0degrees C. for 30 minutes and then warmed to 20–25 degrees C. After 4hours, the reaction is concentrated under reduced pressure and ispartitioned between ethyl acetate and water. The aqueous phase isseparated and extracted with ethyl acetate (3×15 mL), the combinedorganic phases are dried over magnesium sulfate, and concentrated underreduced pressure. The concentrate is purified by flash chromatography(silica; methylene chloride/methanol/ammonium hydroxide 96/3/0.5) togiveN¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³-[4-(benzyloxy)butyl]-5-methyl-N³-propylisophthalamide(X) NMR (300 MHz, Acetone-d₆): _(delta) 7.99–6.74), 5.01 4.51–4.29,4.36, 4.01, 3.80, 3.55–3.16, 2.98–2.82, 2.65–2.62, 2.36, 1.85–1.29, 1.01and 0.68; ESI-MS (m/z) [M+H]⁺=772.

Step 9. A mixture ofN¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³-[4-(benzyloxy)butyl]-5-methyl-N³-propylisophthalamide(X, 100 mg, 0.130 mmol) and palladium on carbon (10%, 100 mg) inabsolute glacial acetic acid (5 mL) is shaken under an atmosphere ofhydrogen at 35 psi for 5 hours. The resulting mixture is filteredthrough diatomaceous earth and washed with methanol. The combinedfiltrates are concentrated under reduced pressure. The concentrate ispurified by flash column chromatography (silica; gradent ofdichloromethane/methanol/ammonium hydroxide 97/3/0.05 to 93/7/0.05) togive the title compound: NMR (300 MHz, CD₃OD): δ 7.55–6.64, 4.19,3.99–3.72, 3.63–3.36, 3.21–3.09, 2.79–2.69, 2.39, 1.90–1.40, 1.29 and1.02–0.6; ESI-MS (m/z) [M+H]⁺=592.

Example 755N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³-(3-hydroxypropyl)-5-methyl-N³-propylisophthalamide(X)

Following the general procedure of EXAMPLE 754 and making non-criticalvariations, but using3-{[[3-(benzyloxy)propyl](propyl)amino]carbonyl}-5-methylbenzoic acid(IX) in place of3-{[[4-(benzyloxy)butyl](propyl)amino]-carbonyl}-5-methylbenzoic acid(IX), the title compound is obtained, ESI-MS (m/z) [M+H]⁺=578.

Example 756N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Step 1. To a stirred mixture of3-[(dipropylamino)carbonyl]-5-methylbenzoic acid (IX, 150 mg, 0.570mmol),(2R,3S)-3-amino-4-[4-(benzyloxy)phenyl]-1-[(3-methoxybenzyl)amino]-2-butanolhydrochloride (VIII, 274 mg, 0.571 mmol), N,N-diisopropylethylamine (400microliter, 2.28 mmol), and HOBt (116 mg, 0.857 mmol) in dichloromethane(10 mL) is added EDC (165 mg, 0.857 mmol). The resulting mixture isstirred at 20–25 degrees C. for 16 hours. The reaction mixture ispartitioned between dichloromethane and water. The aqueous phase isseparated and extracted with dichloromethane (3×15 mL). The combinedorganic phases are washed with water, dried (magnesium sulfate), andconcentrated under reduced pressure.

Purification by flash column chromatography (silica;dichloromethane/methanol/ammonium hydroxide, 97/3/0.05) givesN¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,ESI-MS (m/z) [M+H]⁺=652.

Step 2. A mixture ofN-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(140 mg, 0.215 mmol) and palladium on carbon (10%, 140 mg) in absoluteglacial acetic acid (5 mL) is shaken under an atmosphere of hydrogen at35 psi for 5 hours The resulting mixture is filtered throughdiatomaceous earth and washed with methanol. The combined filtrates areconcentrated under reduced pressure. The concentrate is purified byflash column chromatography (silica; methylenechloride/methanol/ammonium hydroxide gradient from 97/3/0.05 to93/7/0.05) to give the title compound, IR (KBr) 2962, 2931, 1611, 1594and 1263 cm⁻¹; ESI-MS (m/z) [M+H]⁺=562.

EXAMPLE 757

N¹-((1S,2R)-1-benzyl-3-{[3-(2,4-dimethylphenyl)propyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide(X)

Step 1: A stirred mixture of tert-butyl(1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V, 247 mg, 0.939 mmol),sodium carbonate (299 mg, 2.82 mmol), and3-(2,4-dimethylphenyl)propylamine (VI, 628 mg, 2.82 mmol) is heated atreflux overnight. The reaction mixture is cooled to 20–25 degrees C. andconcentrated under reduced pressure. Purification by flash columnchromatography (silica; methylene chloride/methanol/ammonium hydroxide,98/2/1) gives tert-butyl(1S,2R)-1-benzyl-3-{[3-(2,4-dimethylphenyl)propyl]amino}-2-hydroxypropylcarbamate(VII), NMR (300 MHz, CD₃OD): delta 7.22–7.16, 3.81, 3.18, 2.77, 2.54,2.15, 2.13, 1.89 and 1.23.

Step 2: To a stirred mixture of tert-butyl(1S,2R)-1-benzyl-3-{[3-(2,4-dimethylphenyl)propyl]amino}-2-hydroxypropylcarbamate(VII, 180 mg, 0.423 mmol) in dioxane (2 mL) is added hydrochloric acid(0.32 mL of a 4 N mixture in dioxane, 1.27 mmol). The reaction mixtureis stirred overnight and concentrated under reduced pressure to give(2R,3S)-3-amino-1-{[3-(2,4-dimethylphenyl)propyl]amino}-4-phenyl-2-butanolhydrochloride (VIII), NMR (300 MHz, CDCl₃): delta 7.14, 3.73, 2.70, 2.32and 1.86.

Step 3: To a stirred mixture of(2R,3S)-3-amino-1-{[3-(2,4-dimethylphenyl)propyl]amino}-4-phenyl-2-butanolhydrochloride (VIII, 163 mg, 0.411 mmol),3-[(dipropylamino)carbonyl]-5-methylbenzoic acid (IX, 108 mg, 0.411mmol), HOBt (55 mg, 0.411 mmol), and N-methylmorpholine (133 mg, 1.32mmol) in methylene chloride (5 mL) is added EDC (142 mg, 0.740 mmol).The reaction mixture is stirred overnight and then partitioned betweenethyl acetate and water. The organic phase is washed with hydrochloricacid (1 N), saturated sodium bicarbonate, saline, dried (sodiumsulfate), filtered, and concentrated under reduced pressure.Purification by flash column chromatography (silica; methylenechloride/methanol/ammonium hydroxide, 95/5/1) gives the title compound,IR (ATR): 3299, 2930 and 1614 cm⁻¹; APCI-MS (m/z) [M+H]⁺=572.

Example 758N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(4-methylphenyl)propyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamidehydrochloride (X)

Following the general procedure of EXAMPLE 757 and making non-criticalvariations, but using 3-(4-methylphenyl)propylamine in place of3-(2,4-dimethylphenyl)propylamine, the title compound is obtained, IR(ATR): 3282, 2929 and 1594 cm⁻¹; APCI-MS (m/z) [M+H]⁺=558.

Example 759N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5, and 6 and makingnon-critical variations but using tert-butyl(1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V) and3-methoxybenzylamine (VI) and “5-Me-PHTH” (IX), the title compound isobtained, MS [M+H]⁺=546.3.

Example 760N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1,3-dioxo-2-propyl-5-isoindolinecarboxamide(X)

Following the general procedure of EXAMPLEs 4, 5, and 6 and makingnon-critical variations but using tert-butyl(1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V) and3-methoxybenzylamine (VI) and 1,3-dioxo-2-propylisoindoline-5-carboxylicacid (IX), the title compound is obtained, MS [M+H]⁺=516.2.

Example 761N-{(1R,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-bromo-5-methylbenzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using benzyl(1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V) and3-methoxybenzylamine (VI) and 3-bromo-5-methylbenzoic acid (IX), thetitle compound is obtained, MS [M+H]⁺=497.1, 499.1.

Example 7623-bromo-N-{(S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methylbenzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V) and3-methoxybenzylamine (VI) and 3-bromo-5-methylbenzoic acid (IX), thetitle compound is obtained, MS [M+H]⁺=533.3, 535.3.

Example 763N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using benzyl(1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V) and3-methoxybenzylamine (VI) and 3-[(dipropylamino)carbonyl]4-methylbenzoicacid (IX), the title compound is obtained, MS [M+H]⁺=546.4.

Example 764N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V) and3-methoxybenzylamine (VI) and 3-[(dipropylamino)carbonyl]4-methylbenzoicacid (IX), the title compound is obtained, MS [M+H]⁺=582.3.

Example 765N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N¹,N¹-dipropylisophthalamide(X)

3-Bromo-4-methylbenzoic acid (10.94 g, 43.25 mmol), copper(I)cyanide(7.75 g, 86.5 mmol) and 1-methyl-2-pyrrolidinone (75 ml) are heated to160 degrees C. overnight. The mixture is cooled and vacuum distilled togive a residue which is stirred in hydrochloric acid (6N, 60 ml) for 10minutes. The resulting solid is collected by filtration, washed withwater, ether, and dried. The solid is heated to 90 degrees C. in sodiumhydroxide (2N, 250 ml) for 3 hours and the mixture is then cooled andstirred overnight at 20–25 degrees C. The reaction is acidified to aboutpH 3 with concentrated hydrochloric acid which gives a precipitate. Thesolids are collected by filtration and washed with water, thentriturated in boiling water, filtered and dried in a vacuum oven at 60degrees C. The solid is dissolved in methanol (75 ml) and concentratedhydrochloric acid (5 ml) is added and the mixture is refluxed overnight.The mixture then is cooled and concentrated under reduced pressure.Chromatography (silica gel; methanol/methylene chloride, 8/92) gives5-(methoxycarbonyl)-2-methylbenzoic acid.

To 5-(methoxycarbonyl)-2-methylbenzoic acid (250 mg, 1.3 mmol) andtriethylamine (0.72 ml, 5.2 mmol) in methylene chloride (14 ml) is addeddiethylcyanopyrocarbonate (90%, 0.24 ml, 1.4 mmol) with stirring. After1 minute, (2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanoldihydrochloride (VIII, 485 mg, 1.3 mmol) is added and the reaction isstirred overnight. The mixture is concentrated followed bychromatography (silica gel; methanol/methylene chloride 8/92) to afford3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-4-methylbenzoate.

3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]4-methylbenzoate (200 mg, 0.42 mmol) is treated with lithiumhydroxide (39 mg, 0.96 mmol) in tetrahydrofuran/methanol/water (2/1/1, 2ml), and the mixture stirred overnight at 20–25 degrees C. The mixtureis decanted and the supernatant concentrated to give3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-4-methylbenzoicacid.

3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-4-methylbenzoic acid (124 mg, 0.27 mmol) is dissolved intriethylamine (0.07 ml, 0.54 mmol) and methylene chloride (3 ml) andtreated with diethylcyanopyrocarbonate (90%, 0.06 ml, 0.32 mmol) withstirring for 2 minutes. Dipropylamine (0.04 ml, 0.32 mmol) is added andstirring continued overnight. The organic phase is diluted withmethylene chloride and washed with saturated sodium bicarbonate (2×50ml) and saline (50 ml) then dried over anhydrous sodium sulfate,filtered and concentrated. Chromatography (silica gel;methanol/methylene chloride, 8/92) gives the title compound, MS[M+H]⁺=546.3.

Example 766N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(2-furyl)-5-methylbenzamide(X)

N-{(1R,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-bromo-5-methylbenzamide(X, EXAMPLE 761, 295 mg, 0.59 mmol), 2-furanylboronic acid (133 mg, 1.19mmol) and sodium carbonate (366 mg, 2.95 mmol) are combined indimethylformamide (5 ml) and sparged under a flow of nitrogen for 15minutes. Tetrakis(triphenylphosphino)palladium (136 mg, 0.12 mmol) isadded and the mixture heated to 100 degrees C. overnight. The mixture iscooled to 20–25 degrees C., diluted with chloroform (50 ml) andextracted with water (3×100 ml). The organic phase is separated andwashed with saturated sodium bicarbonate (2×100 ml) and saline (100 ml),dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. The residue is chouromatographed (silica gel;methanol/methylene chloride, 8/92) to give the title compound, MS[M+H]⁺=485.3.

Example 767N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3′,5,5′-trimethyl-1,1′-biphenyl-3-carboxamide(X)

Following the general procedure of EXAMPLE 766 and making non-criticalvariations but using 3,5-dimethylphenylboronic acid, the title compoundis obtained, MS [M+H]⁺=523.3.

Example 7683′-Acetyl-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl[1,1′-biphenyl]-3-carboxamide(X)

Following the general procedure of EXAMPLE 766 and making non-criticalvariations but using 3-acetylphenylboronic acid, the title compound isobtained, MS [M+H]⁺=537.3.

Example 769N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3′-methoxy-5-methyl[1,1′-biphenyl]-3-carboxamide(X)

Following the general procedure of EXAMPLE 766 and making non-criticalvariations but using 3-methoxyphenylboronic acid, the title compound isobtained, MS [M+H]⁺=525.3.

Example 770N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl[1,1′-biphenyl]-3-carboxamide(X)

Following the general procedure of EXAMPLE 766 and making non-criticalvariations but using phenylboronic acid, the title compound is obtained,MS [M+H]⁺=495.3.

Example 771 3-Methyl-5-(3-thienyl)benzoic acid (IX)

Following the general procedure of EXAMPLE 766 and making non-criticalvariations but using 2-thiopheneboronic acid and methyl3-bromo-5-methylbenzoate, methyl 3-methyl-5-(3-thienyl)benzoate isobtained.

Methyl 3-methyl-5-(3-thienyl)benzoate (257 mg, 1.1 mmol) is treated withlithium hydroxide (186 mg, 4.4 mmol) in tetrahydrofuran/methanol/water(8 ml, 2:1:1) and the mixture is stirred for 2 hours at 20–25 degrees C.The mixture is acidified and concentrated to give the title compound, MS[M+H]⁺=217.0.

Example 772N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(3-thienyl)benzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using benzyl(1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V) and3-methoxybenzylamine (VI) and 3-methyl-5-(3-thienyl)benzoic acid (IX),the title compound is obtained, MS [M+H]⁺=501.2.

Example 773N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(2-thienyl)benzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using benzyl(1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V) and3-methoxybenzylamine (VI) and 3-methyl-5-(2-thienyl)benzoic acid, thetitle compound is obtained, MS [M+H]⁺=501.2.

Example 774N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(3-thienyl)benzamide (X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V) and3-methoxybenzylamine (VI) and 3-methyl-5-(3-thienyl)benzoic acid (IX),the title compound is obtained, MS [M+H]⁺=537.2.

Example 775N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-methyl-5-(3-thienyl)benzamide(X)

Following the general procedure of EXAMPLEs 4, 5 and 6 and makingnon-critical variations but using tert-butyl(1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V) and3-iodobenzylamine (VI) and 3-methyl-5-(3-thienyl)benzoic acid (IX), thetitle compound is obtained, MS [M+H]⁺=633.1.

Example 776N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-3-(3-thienyl)benzamide(X)

Following the general procedure of EXAMPLEs 4, 5, 6 and 766 and makingnon-critical variations but using benzyl(1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V) and3-methoxybenzylamine (VI) and 3-bromo-4-methylbenzoic acid (IX) and3-thiopheneboronic acid, the title compound is obtained, MS[M+H]⁺=501.2.

Example 777N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³N³,N⁵,N⁵-tetrapropylbenzene-1,3,5-tricarboxamidehydrochloride (X)

Following the general procedures of CHART A as well as PREPARATIONs1–13, EXAMPLEs 1–13, 321–48–579, 597–622 and 624–631 and makingnon-critical variations and using the appropriate reagents, the titlecompound is obtained, HRMS (FAB)=659.4155.

Example 778N¹-{(1S,2R)-1-(3,5-Difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylbenzene-1,3,5-tricarboxamide(X)

Following the general procedures of CHART A as well as PREPARATIONs1–13, EXAMPLEs 1–13, 321–48–579, 597–622 and 624–631 and makingnon-critical variations and using the appropriate reagents, the titlecompound is obtained, MS (M+H)⁺=609.2.

Example 779 Ethyl3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-[(dipropylamino)carbonyl]benzoatehydrochloride (X)

Following the general procedures of CHART A as well as PREPARATIONs1–13, EXAMPLEs 1–13, 32148–579, 597–622 and 624–631 and makingnon-critical variations and using the appropriate reagents, the titlecompound is obtained, HRMS (FAB)=604.3392.

Example 780N¹-{(1S,2R)-2-Hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropylbenzene-1,3,5-tricarboxamide(X)

Following the general procedures of CHART A as well as PREPARATIONs1–13, EXAMPLEs 1–13, 32148–579, 597–622 and 624–631 and makingnon-critical variations and using the appropriate reagents, the titlecompound is obtained, MS (M+H)⁺=591.0.

Example 781N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide(X)

Following the general procedures of CHART A and CHART T as well asPREPARATIONs 1–13, EXAMPLEs 1–13, 321–48–579, 597–622 and 624–631 andmaking non-critical variations and using the appropriate reagents, thetitle compound is obtained, MS (M+H)⁺=679.2.

Example 7825-Amino-N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide(X)

Following the general procedures of CHART A and CHART T as well asPREPARATIONs 1–13, EXAMPLEs 1–13, 321–48–579, 597–622 and 624–631 andmaking non-critical variations and using the appropriate reagents, thetitle compound is obtained, MS (M+H)⁺=547.3.

Example 783N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(trifluoroacetyl)amino]isophthalamide(X)

Following the general procedures of CHART A and CHART T as well asPREPARATIONs 1–13, EXAMPLEs 1–13, 32148–579, 597–622 and 624–631 andmaking non-critical variations and using the appropriate reagents, thetitle compound is obtained, MS (M+H)⁺=643.2.

Example 784N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamidehydrochloride (X)

Following the general procedures of CHART A and CHART T as well asPREPARATIONs 1–13, EXAMPLEs 1–13, 32148–579, 597–622 and 624–631 andmaking non-critical variations and using the appropriate reagents, thetitle compound is obtained, MS (M+H)⁺=625.0.

Example 785N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(thien-2-ylsulfonyl)amino]isophthalamidehydrochloride (X)

Following the general procedures of CHART A and CHART T as well asPREPARATIONs 1–13, EXAMPLEs 1–13, 321–48–579, 597–622 and 624–631 andmaking non-critical variations and using the appropriate reagents, thetitle compound is obtained, MS (M+H)⁺=693.1.

Example 786N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(thien-2-ylcarbonyl)amino]isophthalamide(X)

Following the general procedures of CHART A and CHART T as well asPREPARATIONs 1–13, EXAMPLEs 1–13, 321–48–579, 597–622 and 624–631 andmaking non-critical variations and using the appropriate reagents, thetitle compound is obtained, MS (M+H)⁺=657.2.

Example 787N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(methacryloylamino)-N³,N³-dipropylisophthalamide(X)

Following the general procedures of CHART A and CHART T as well asPREPARATIONs 1–13, EXAMPLEs 1–13, 321–48–579, 597–622 and 624–631 andmaking non-critical variations and using the appropriate reagents, thetitle compound is obtained, MS (M+H)⁺=615.1.

Example 788N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(2,2-dimethylpropanoyl)amino]-N³,N³-dipropylisophthalamide(X)

Following the general procedures of CHART A and CHART T as well asPREPARATIONs 1–13, EXAMPLEs 1–13, 32148–579, 597–622 and 624–631 andmaking non-critical variations and using the appropriate reagents, thetitle compound is obtained, MS (M+H)⁺=631.3.

Example 789N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(phenylsulfonyl)amino]-N³,N³-dipropylisophthalamide(X)

Following the general procedures of CHART A and CHART T as well asPREPARATIONs 1–13, EXAMPLEs 1–13, 321–48–579, 597–622 and 624–631 andmaking non-critical variations and using the appropriate reagents, thetitle compound is obtained, MS (M+H)⁺=687.2.

Example 790N-{(I1S,2R)-l1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(methylthio)pentanamide

Following the general procedure of EXAMPLEs 588–592 and 597–619 andusing the appropriate starting materials the title compound is obtained,HRMS m/z calculated for C₂₄H₃₅N₂O₃S (M+H)=431.2363, found=431.2397.

Example 791 tert-butyl(2R,3S)-3-({3-[(dipropylamino)sulfonyl]-propanoyl}amino)-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)carbamate

Following the general procedure of EXAMPLEs 588–592 and 597–619 andusing the appropriate starting materials the title compound is obtained,HRMS calculated for M+H is 620.3369, observed=620.3379.

Example 792 2-Butylcyclopropylamine hydrochloride (VI)

A solution of triethylphosphonoacetate (22.4 g, 0.1I mol) in 13 mL ofdiglyme is added to a mixture of 13 mL of diglyme and sodium hydride(60%, 5.7 g, 0. 12 mol) in mineral oil. When hydrogen evolution ceased,1,2-epoxyhexane (12 g, 0.12 mol) in diglyme (12 mL) is added. Themixture is stirred for I day at 25 degrees C. and 3 hours at 140 degreesC. A mixture of sodium hydroxide (15 g in 25 mL of water) is added inthe cold. The mixture is refluxed 15 hours, diluted with cold water (100mL), and washed with ether (3×50 mL). Acidification to pH=2 withsulfuric acid (25%), extraction with ether (5×25 mL), drying the etherover anhydrous sodium sulfate, filtration and concentration gives2-butylcyclopropanecarboxylic acid. The acid (5.0 g, 0.035 mmol) indichloromethane (15 mL) is heated with thionyl chloride (5.1 g, 3.1 mL)for 15 hours at 60 degrees C. The reaction mixture is distilled (76degrees C.–80 degrees C.) to give the acid chloride which is dissolvedin acetone (15 mL), cooled to −10 degrees C. and treated with sodiumazide (2.2 g, 33.8 mmol) in water (5 mL). The reaction mixture isstirred at −10 degrees C. for another 1 hour and then poured ontoice/water, extracted with ether (3×10 mL), dried, and cautiouslyevaporated to dryness at 20–25 degrees C. under reduced pressure. Theresidue is dissolved in toluene (15 mL) and carefully warmed to 100degrees C. while vigorously stirring for 1 hour. Concentratedhydrochloric acid (7 mL) is added and the reaction mixture is refluxedfor 15 minutes. The acidic layer is evaporated to dryness to give thetitle compound, MH⁺=114.2.

Example 793 2-Aminomethyl-3-methylfuran (VI)

3-Methylfuroic acid (4.0 g, 32 mmol) is dissolved in DMF (10 mL) at20–25 degrees C., and 1,1-carbonyldiimidazole (5.7 g, 35 mmol) is added.After 15 minutes, ammonia is bubbled into the mixture for approximately2 minutes. This mixture is stirred at 20–25 degrees C. for 2 hours thenthe mixture is concentrated under reduced pressure. The residue ispartitioned between ethyl acetate and 10% aqueous citric acid. Thelayers are separated, and the aqueous layer extracted with additionalethyl acetate (2×). The combined organic phases are washed withsaturated sodium bicarbonate, then saline and dried over magnesiumsulfate, filtered and concentrated. Crystals formed upon standing, whichare isolated by filtration and washing with a small amount of ethylacetate/hexanes (80/20), MS(ESI): MH+: 126.1. 3-Methylfuroic amide (317mg, 2.5 mmol) is dissolved in dry THF (5 mL). Lithium aluminum hydride(230 mg, 6.0 mmol) is added in one portion, and the mixture heated toreflux overnight. The mixture is cooled to 0 degrees C., and quenched byaddition of THF/water (50/50). The mixture is then diluted with THF, andfiltered through diatomaceous earth. The filtrate is concentrated togive the title compound, MS(ESI): (M−H)+: 109.1.

Example 794 4-Aminomethyl-3,5-dimethylisoxazole (VI)

4-Chloromethyl-3,5-dimethylisoxazole (700 mg, 4.8 mmol) is suspended inconcentrated aqueous ammonia at 20–25 degrees C., and vigorously stirredovernight. The reaction mixture is extracted with isopropylalcohol/chloroform (10/90, 2×). The combined organic phases areconcentrated under nitrogen flow. The residue is purified by flashchromatography methanol/methylene chloride (5–20%, 1% triethylamine) togive the title compound, MR (CDCl₃, 300 MHz) delta3.62, 2.37, 2.29, and1.44.

Example 795 5-Hydroxymethyl-2-(2-methylpropyl) thiazole (VI)

Isovalerothioamide is synthesized according to the procedure in J. Med.Chem. 41, 602–617 (1998). Isovaleramide (10 g, 9.9 mmol) is suspended indry ether (400 mL), then phosphorous(V) sulfide (4.4 g, 0.99 mmol) isadded in portions. This is vigorously stirred at 20–25 degrees C. for 2hours, then filtered. The filtrate is concentrated under reducedpressure and the residue used without further purification: MS(ESI):MH+: 118.1.

Isovalerothioamide (6.0 g, 51 mmol) and ethyl formylchloroacetate(Heterocycles 32 (4), 693–701, (1991), 5.0 g, 33 mmol) are dissolved indry DMF (20 mL), and heated to 95 degrees C. for 4 hours. The reactionis subsequently cooled to 0 degrees C., and cold water (50 mL) is added.The mixture is basified to pH=8 with solid sodium bicarbonate, thenextracted with ether (3×35 mL). The combined organic extracts are washedwith water, then saline and dried over magnesium sulfate, filtered, andconcentrated. The residue is purified by flash chromatography (ethylacetate/hexanes 4–10% elution) to give the desired product. NMR (CDCl₃,300 MHz) δ 8.27, 4.45–4.30, 3.70–3.50, 3.00–2.80, 2.30–2.10, 1.40–1.20,and 1.10–0.90.

A solution of ethyl 2-(2-methylpropyl)thiazole-5-carboxylate (2.05 g,9.6 mmol) in THF (10 mL) is added dropwise with stirring to a suspensionof lithium aluminum hydride (730 mg, 19 mmol) in dry THF (50 mL) at 0degrees C. Upon complete addition, the reaction mixture is allowed tostir at 20–25 degrees C. The reaction mixture is cooled to 0 degrees C.,and water (0.75 mL), aqueous sodium hydroxide (15%, 0.75 mL), and water(2.25 mL) is added in succession. This mixture is stirred at 0 degreesC. for 1 hour, then filtered through diatomaceous earth, (THF andchloroform). The filtrate is concentrated to give5-hydroxymethyl-2-(2-methylpropyl)thiazole, MS(ESI): MH+: 172.1.

Example 796 3-(2-Methylpropyl)-5-aminomethylisoxazole (VI)

Isovaleraldehyde (5.4 mL, 50 mmol) and hydroxylamine hydrochloride (3.5g, 50.4 mmol) are vigorously stirred in water (6 mL). To this is added asolution of sodium carbonate (2.65 g, 25 mmol) in water (15 mL). This isvigorously stirred overnight. The mixture is extracted with ether. Theorganic layer is washed with water, then dried over sodium sulfate,filtered and concentrated. This is used in subsequent reactions withoutfurther purification: MS(ESI): MH+: 102.1.

Propargylamine (8.0 mL, 117 mmol) is dissolved in methylene chloride (60mL), and di-tert-butyl dicarbonate (25 g, 114 mmol) is added. This isstirred overnight, and concentrated to provide the BOC-protectedpropargylamine, which is used without further purification: MS(ESI):MNa+: 178.0.

BOC-propargylamine (6.2 g, 39.7 mmol) and isovaleroxime (3.97 g, 39.3mmol) is dissolved in methylene chloride (60 mL), and triethylamine(0.55 mL, 3.95 mmol) is added. This is cooled to 0 degrees C., andbleach (5% aqueous solution, 59.1 g) is added dropwise with vigorousstirring. After addition is complete, the mixture is allowed to warm to20–25 degrees C. over 22 hours. The layers are separated, and theaqueous layer is extracted with methylene chloride (2×). The combinedorganic extracts are washed with saline, dried over magnesium sulfate,filtered and concentrated. The residue is purified by chromatography(silica gel, ethyl acetate/hexanes 5–10%) to give the BOC-protectedtitle compound, MS(ESI): MH+: 255.3.

BOC-protected 3-(2-methylpropyl)-5-aminomethylisoxazole (2.4 g, 9.3mmol) is dissolved in methylene chloride (10 mL) and treated withtrifluoroacetic acid (10 mL) at 20–25 degrees C. This is stirred at20–25 degrees C. for 70 minutes, then concentrated. The product isdissolved in methylene chloride, and washed with aqueous potassiumcarbonate (1 M) until basic (pH=11). The organic layer is isolated,dried over sodium sulfate, filtered and concentrated to give the titlecompound: MS(ESI): MH+: 155.2.

Example 797 tert-butyl (3R)-2-oxo-1-propylazepanylcarbamate (VI)

To N-t-Boc-D-Lys-OH (10 g, 41.4 mmole) in DMF (4 liters) is addedbenzotriazol-1yloxytripyrrolidino-phosphonium hexafluorophosphate (BOP,18.3 g, 41.4 mmole) and sodium bicarbonate (17.4 g, 206.8 mmole); thereaction is stirred at 20–25 degrees C. for 12 hours. The reaction isthen concentrated to 50 ml volume and diluted with ethyl acetate andwashed with sodium bicarbonate 3×, water, 1M potassium bisulfate andbrine, dried and concentrated. Purification by chromatography on silicagel afforded 5.05 g of the tert-butyl (3R)-2-oxoazepanylcarbamate as asolid; the procedure employed is similar to that described inJ.Med.Chem. 1999, 4193. M+H-(t-Boc) (m/e=129.2), M+Na (m/e=251.1).

To the above lactam (2 g, 8.77 mmole) in dry THF (20 ml) is addedn-butyllithium /hexane (2.5 M, 5.3 ml, 13.2 mmole) at −78 degrees C.,the reaction is stirred for 1 hour and 1-bromopropane (3.2 ml, 35.1mmole) is added. The reaction is stirred for 1 hour and the cold bathremoved and stirring continued for another 16 hours. Tetrabutylammoniumiodide (0.49 g, 2.63 mmole) is added and the reaction stirred foranother 16 hours. The reaction is partitioned between ethylacetate/hydrochloric acid +ice +water, the mixture is washed with waterand saline and concentrated. Purification by chromatography on silicagel afforded the title compound, MS (M+Na+) 293.3.

Example 798N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide(X)

Following the procedure described in J Am. Chem. Soc. 1986, 3150, thetrifluoroacetic acid salt ofN¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide(92.9 mg, 0.117 mmol) is dissolved in triethylamine (0.2 M, 0.6 mL)before the addition of PdCl₂(PPh₃)₂ (3.3 mg, 0.005 mmol), and copper (I)iodide (1.1 mg, 0.006 mmol). The reaction is heated to reflux. While thereaction is refluxing, trimethylsilylacetylene (0.02 ml, 0.14 mmol) isadded via syringe. The reaction is refluxed for 3 hour under N₂ (g), andthe reaction cooled to 20–25 degrees C. before partitioning betweenaqueous sodium bicarbonate and ethyl acetate. The product is extractedwith ethyl acetate (3×), washed with saline, dried over sodium sulfate₄,and filtered before the removal of solvent under reduced pressure.

The TMS protected acetylene (0.117 mmol) is dissolved in methanol (0.2M, 0.5 mL) before the addition of potassium hydroxide (1M, 0.7 mL, 0.7mmol). The reaction is stirred at 20–25 degrees C. for 6 hours, at whichpoint the mixture is partitioned between sodium bicarbonate and ethylacetate. The product is extracted with ethyl acetate (3×), washed withsaline, dried over sodium sulfate, and filtered before the removal ofsolvent under reduced pressure. Column chromatography (silica gel;1.5–2% isopropanol/chloroform under basic conditions; a few drops ofammonium hydroxide per 100 mL of elution solvent) gives the titlecompound, MS m/z (M+H)⁺=576.3.

Example 799 1-phenylcyclopropylamine (VI)

Following the procedure described in N. W. Werner et.al., J. Org. Syn.Coll. Vol. 5, 273–276, sodium azide (0.915g, 14.1 mmol) is slowly addedto a solution of 1-phenyl-cyclopropanecarboxlic acid (1.0 g, 6.1 mmol)in concentrated sulfuric acid (5 ml) and dichloromethane (10 ml). Thesodium sulfate precipitated out of solution. The reaction mixture isheated to 50 degrees C. for 17 hours and then cooled to 0 degrees C. Themixture is basified to pH=11 with sodium hydroxide (1N) and extractedwith dichloromethane (2×). The organic layers are combined, dried oversodium sulfate, filtered and concentrated. The residue is purified bychromatography (silica gel; isopropyl alcohol/chloroform/ammoniumhydroxide 4/95/1) to give the title compound, MS (ESI+) for C₉H₁₁N m/z(M+H)⁺=134.

Example 800 7-methoxy-1,2,3,4-tetrahydro-1-naphthalenamine (VI)

7-Methoxy-1-tetralone (2.0 g, 11.3 mmol), hydroxylamine hydrochloride(1.56 g, 22.6 mmol) and sodium acetate (1.8g, 22.6 mmol) are suspendedin ethanol/water (3/1, 40 mL). The mixture is heated for 45 min. at 100degrees C. The mixture is allowed to cool overnight and the precipitateobtained is filtered and washed with water to yield an intermediateoxime, MS (ES) (M+H): 192.1. The oxime is dissolved in glacial aceticacid (25 ml) and palladium/carbon (500 mg) is added and the mixturehydrogenated under 50 psi at 20–25 degrees C. overnight. The catalyst isfiltered over diatomaceous earth and washed with methanol. The combinedfiltrates are concentrated. The concentrate is triturated with ether togive the title compound, MS (CI) (MH+): 178.2.

Example 8013-Amino-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-methylbutanamidedihydrochloride

Following the general procedure of EXAMPLE 6 and making non-criticalvariations but starting with(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]4-phenyl-2-butanol (VIII) andreacting it with 3-[(tert-butoxycarbonyl)amino]-2-methylbutanoic acid(IX), and then treatment with HCl, the title compound is obtained, HRMScalculated =400.2600, observed=400.2596.

Example 802N-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-ethylhexanamidehydrochloride

Following the general procedure of EXAMPLE 6 and making non-criticalvariations but starting with(2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanol (VIII) andreacting it with 2-ethylhexanoic acid (IX), the title compound isobtained, HRMS calculated=427.2961, observed=427.2961.

Example 803N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-[(isobutylsulfonyl)amino]propanamidetrifluoroacetate

Following the general procedure of CHART I and making non-criticalvariations but starting with(2R,3S)-3-amino-1-[(3-iodobenzyl)amino]-4-phenyl-2-butanol (VIII) andreacting it with N-(isobutylsulfonyl)-beta-alanine (IX), the titlecompound is obtained, HRMS calculated=588.1393, observed=588.1379.

Example 804N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³-(isobutylsulfonyl)-beta-alaninamidetrifluoroacetate

Following the general procedure of CHART I and making non-criticalvariations but starting with(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-iodobenzyl)amino]-2-butanol(VII) and reacting it with N-(isobutylsulfonyl)-beta-alanine (IX), thetitle compound is obtained, M+H=624.

Example 8055-bromo-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³,N³-dipropylisophthalamidehydrochloride

Following the general procedure of EXAMPLE 6 and making non-criticalvariations but starting with(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-iodobenzyl)amino]-2-butanol(VIII) and reacting it with 3-bromo-5-[(dipropylamino)carbonyl]benzoicacid (IX), the title compound is obtained, M+H=745.

Example 806N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide

Following the general procedure of EXAMPLE 6 and making non-criticalvariations but starting with(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(1-phenylcyclopropyl)amino]-2-butanol(VIII) and reacting it with 3-[(dipropylamino)carbonyl]-5-methylbenzoicacid (IX), the substituted amine (X) is obtained. MH⁺=578.

Example 806.15-bromo-N¹-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide

Following the general procedure of EXAMPLE 6 and making non-criticalvariations but starting with(2R,3S)-3-amino-1-[(3-bromobenzyl)amino]4-(3,5-difluorophenyl)-2-butanolhydrochloride (VIII) and reacting it with3-bromo-5-[(dipropylamino)carbonyl]benzoic acid (IX), the title compoundis obtained, NMR (500 MHz, CD₃OD): δ 7.85, 7.72, 7.69, 7.67, 7.52, 7.51,6.88, 6.86, 6.74, 4.39–4.13, 3.95–3.88, 3.53–2.96, 2.82, 1.70, 1.50,0.99 and 0.71.

Examples 807–1,064

Following the general procedure of CHART A and EXAMPLES 4–6, 321–327,329–464, 466–527, 529–579, 597–619 and 633–708 and making non-criticalvariations, and using the appropriate amines (VIII) and amide formingagents (IX), the titled compounds are obtained.

EXAMPLE Substituted Amine (X) 807N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(2-propylpentanoyl)benzamide808N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(2-ethylpentanoyl)-5-methylbenzamide809N-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-methyl-5-(2-propylpentanoyl)benzamide810N-{(1S,2R)-1-benzyl-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-3-methyl-5-(2-propylpentanoyl)benzamide811N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(2-ethylbutanoyl)-5-methylbenzamide812N¹-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(2-propylpentanoyl)isophthalamide813N-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(2-ethylpentanoyl)-5-methylbenzamide814N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(2-propylpentanoyl)isophthalamide815N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]proyl}-5-(2-propylpentanoyl)isophthalamide816N-[(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propyl]-3-methyl-5-(2-propylpentanoyl)benzamide817N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(2-propylpentanoyl)benzamide818N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-methyl-5-(2-propylpentanoyl)benzamide819N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(3-pyridinyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide820N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(4-pyridinyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide821N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1-propynyl)isophthalamide822N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-diproyl-5-(1-propynyl)isophthalamide823N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-(2-propynyl)isophthalamide824N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(2-propynyl)isophthalamide825N¹-{(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide826N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(3-thienylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide827N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide828N¹-{(1S)-1-[(1R)-2-(benzylamino)-1-hydroxyethyl]-3-butynyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide829N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide830N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(2-thienylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide831N¹-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide832N¹-{(1S,2R)-3-(benzylamino)-1-[4-(benzyloxy)benzyl]-2-hydroxypropyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide833N¹-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide834N¹-[(1S,2R)-3-(benzylamino)-1-(cyclohexylmethyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide835N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide836N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(1-naphthylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide8372,3,5-trideoxy-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-methoxybenzyl)amino]-1-S-phen-yl-1-thio-D-erythouro-pentitol 838N¹-[(1S,2R)-3-(benzylamino)-1-(3-furylmethyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide839N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-methylbutyl)-5-methyl-N³,N³-dipropylisophthalamide840N¹-[(1S,2R)-3-(benzylamino)-1-(4-flouorobenzyl)-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide841N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide842N¹-[(1S,2R)-3-(benzylamino)-1-(2-furylmethyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide843N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide844N¹-{(1S)-1-[(1R)-2-(benzylamino)-1-hydroxyethyl]-3-methylbutyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide845N¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide846N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(4-hydroxybenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide847N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-butynyl)-5-methyl-N³,N³-dipropylisophthalamide848N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-butynyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide8495-(benzylamino)-2,3,5-trideoxy-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-S-phenyl-1-thio-D-erythouro-pentitol850N¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide851N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(4-hydroxybenzyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide852N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide853N¹-{(1S)-1-[(1R)-2-(benzylamino)-1-hydroxyethyl]-3-methylbutyl}-5-methyl-N³,N³-dipropylisophthalamide854N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide855*N¹-[(1S,2R)-3-(benzylamino)-1-(3-furylmethyl)-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide856N¹-((1S)-1-[(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-methylbutyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide857N¹-[(1S,2R)-3-(benzylamino)-1-(4-fluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide858N¹-[(1S,2R)-3-(benzylamino)-1-(2-furylmethyl)-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide859N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide860N¹-{(1S,2R)-3-(benzylamino)-2-hydroxy-1-(1-naphthylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide861N¹-{(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide862N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(2-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide863N¹-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide864N¹-{(1S,2R)-3-(benzylamino)-1-[4-(benzyloxy)benzyl]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide865N¹-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide866N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(3-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide867N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide868N¹-{(1S)-1-[(1R)-2-(benzylamino)-1-hydroxyethyl]-3-butynyl}-5-methyl-N³,N³-dipropylisophthalamide869N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide870N¹-{(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide871N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide872N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide873N¹-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide874N¹-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide875N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide876N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-methylbutyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide877N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide878N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide879N¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide880N¹-{(1S,2R)-1-hydroxy-1-[3-(hydroxymethyl)benzyl]-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide881N¹-{(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-[3-(hydroxymethyl)benzyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide882n¹-{(1S,2R)-2-hydroxy-1-[3-(hydroxymethyl)benzyl]-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide883N¹-{(1S,2R)-2-hydroxy-1-[4-(hydroxymethyl)benzyl]-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide884N¹-{(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-[4-(hydroxymethyl)benzyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide885N¹-{(1S,2R)-2-hydroxy-1-[4-(hydroxymethyl)benzyl]-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide886N¹-{(1S,2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide887N¹-[(1S,2R)-3-[(3-ethylbenzyl)amino]-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide888N¹-{(1S,2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide889N¹-{(1S,2R)-1-[3-(benzyloxy)-5-fluorobenzyl]-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide890N¹-{(1S,2R)-1-[3-(benzyloxy)-5-fluorobenzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide891N-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(dipropylamino)sulfonyl]propanamide892N¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide8933-[(dipropylamino)sulfonyl]-N-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]propanamide894N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]-N⁵,N⁵-dipropylpentanediamide8953-[(dipropylamino)sulfonyl]-N-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}propanamide896N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide8973-[(dipropylamino)sulfonyl]-N-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}propanamide898N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide8993-[(dipropylamino)sulfonyl]-N-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}propanamide900N¹-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide9013-[(dipropylamino)sulfonyl]-N-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}propanamide902N¹-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide9033-[(dipropylamino)sulfonyl]-N-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]propanamide904N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]-N⁵,N⁵-dipropylpentanediamide9053-[(dipropylamino)sulfonyl]-N-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]propanamide906N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]-N⁵,N⁵-dipropyl-pentanediamide 907N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-{[(2R)-1-ethylpyrrolidinyl]carbo-nyl}-5-methylbenzamide 908N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-{[(2S)-2-ethylpyrrolidinyl]carbo-nyl}-5-methylbenzamide 909N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(1-ethyl-1H-imidazol-2-yl)carbo-nyl]-5-methylbenzamide 910N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(1-ethyl-4-methyl-1H-imidazol-5-yl)carbo-nyl]-5-methylbenzamide 911N¹((1S,2)-1-(3,5-difluorobenzyl)-2-hydroxy-2-{1-[(3-methoxybenzyl)amino]cyclopropyl}ethyl)-5-methyl-N³,N³-dipropylisophthalamide912N¹-((1S,2)-1-(3,5-difluorobenzyl)-2-{1-[(3-ethylbenzyl)amino]cyclopropyl}-2-hydroxyethyl)-5-methyl-N³,N³-dipropylisophthalamide913(1R,2R,3R)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N²,N²-dipropyl-1,2,3-cyclo-propanetricarboxamide 914(1R,2R,3R)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-phenyl-N²,N²-dipropyl-1,2-cyclo-propanedicarboxamide 915(1R,2R,3R)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-N²,N²-dipropyl-1,2-cyclo-propanedicarboxamide 916(1R,2R,3S)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-N²,N²-dipropyl-1,2-cyclo-propanedicarboxamide 917(1R,2R,3S)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-phenyl-N²,N²-dipropyl-1,2-cyclo-propanedicarboxamide 918(1R,2R,3S)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N²,N²-dipropyl-1,2,3-cyclo-propanetricarboxamide 919(1R,2R,3S)-3-(1-amino-2-oxoethyl)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N²,N²-di-propyl-1,2-cyclopropanedicarboxamide 920(1R,2R,3R)-3-(2-amino-2-oxoethyl)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]-propyl}-N²,N²-di-propyl-1,2-cyclopropanedicarboxamide 921(1R,2R,3S)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[2-(dipropylamino)-2-oxo-ethyl]-3-methylcyclopropanecarboxamide 922(1R,2R,3R)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[2-(dipropylamino)-2-oxo-ethyl]-3-methylcyclopropanecarboxamide 923(1S,2R,3R)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[2-(dipropylamino)-2-oxo-ethyl]-3-phenylcyclopropanecarboxamide 924(1S,2R,3S)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[2-(dipropylamino)-2-oxo-ethyl]-3-phenylcyclopropanecarboxamide 925(1S,2R,3R)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[2-(dipropylamino)-2-oxo-ethyl]-1,2-cyclopropanedicarboxamide 926(1S,2R,3S)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[2-(dipropylamino)-2-oxo-ethyl]-1,2-cyclopropanedicarboxamide 927N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-{[(trifluoro-methyl)sulfonyl]amino}isophthalamide 928N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sul-fonyl]amino}isophthalamide 929N¹-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide930N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-{methyl[(trifluoromethyl)sulfonyl]amino}-N³,N³-di-propylisophthalamide 931N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-{methyl[(trifluoromethyl)sulfonyl]a-mino}-N³,N³-dipropylisophthalamide 932N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-{propyl[(trifluoromethyl)sul-fonyl]amino}isophthalamide 933N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylsuflonyl)amino]-N³,N³-di-propylisophthalamide 934N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(phenylsulfonyl)amino]-N³,N³-di-propylisophthalamide 935N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-3-[(dipropylamino)sulfonyl]propanamide936N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-3-[(dipropylamino)sulfonyl]propanamide937N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(dimethyalmino)benzyl]amino}-2-hydroxypropyl)-3-[(dipropylamino)sulfonyl]propanamide938N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-1,3-thiazol-5-yl)methyl]amino}-2-hydroxypropyl)-3-[(dipropylamino)sul-fonyl]propanamide 939N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isobutyl-1,3-thiazol-5-yl)methyl]amino}propyl)-3-[(dipropyalmino)sul-fonyl]propanamide 940N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-5-isoxazolyl)methyl]amino}propyl)-3-[(dipropylamino)sulfonyl]propanamide941N-[(1S,2R)-3-[(3-cyclopropylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-3-[(dipropylamino)sulfonyl]propanamide942N¹-[(1S,2R)-3-[(3-cyclopropylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide943N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1,3-thiazol-2-yl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide944N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1,3-oxazol-2-yl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide945N¹-[(1S,2R)-3-[(3-acetylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide946N¹-[(1S,2R)-3-[(3-acetylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroyxpropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide947N¹-[(1S,2R)-3-[(3-acetylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-(aminosulfonyl)-N³,N³-dipropylisophthalamide948N¹-[(1S,2R)-3-[(3-acetylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-(methylsuflonyl)-N³,N³-dipropylisophthalamide949N¹-[(1S,2R)-3-{[3-(diethylamino)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide950N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(4-morpholinyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide951N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1-piperazinyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide952N¹-[(1S,2R)-3-{[3-(aminosulfonyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide953N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({3-[(dimethylamino)sulfonyl]benzyl}amino)-2-hydroxypropyl]-5-meth-yl-N³,N³-dipropylisophthalamide 954N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1-piperidinylsulfonyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide955N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(methylsulfonyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide956N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(isopropylsulfonyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide957N¹-[(1S,2R)-3-{[3-(aminocarbonyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide958N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({3-[(dimethylamino)carbonyl]benzyl}amino)-2-hydroxypropyl]-5-meth-yl-N³,N³-dipropylisophthalamide 959N¹-[(1S,2R)-3-[(3-cyanobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide9603-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}meth-yl)phenylcarbamate 9613-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)phenyldimethylcarbamate 962N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1-propynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide963N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(3-methyl-1-butynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide964N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(2-propynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide965N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(5-isobutyl-1,3,4-oxadiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 966N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(5-ethyl-1,3,4-oxadiazol-2-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-propylisophthalamide 967N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(5-ethyl-1,3,4-thiadiazol-2-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-propylisophthalamide 968N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(5-isobutyl-1,3,4-thiadiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 969N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(3-ethyl-1,2,4-thiadiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-propylisophthalamide 970N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(3-isobutyl-1,2,4-thiadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 971N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(3-isobutyl-1,2,4-oxadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 972N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-propylisophthalamide 973N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-1,3-oxazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-propylisophthalamide 974N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isobutyl-1,3-oxazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 975N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-isobutyl-1,3,4-oxadiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 976N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-isobutyl-1,3,4-thiadiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 977N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(5-ethyl-1,3,4-thiadiazol-2-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-proylisophthalamide 978N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(5-ethyl-1,3,4-oxadiazol-2-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-propylisophthalamide 979N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-proylisophthalamide 980N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3-ethyl-1,2,4-thiadiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-propylisophthalamide 981N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-1,2,4-thiadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 982N¹-((1S,2R)-1-(3,5-difluorbenzyl)-2-hydroxy-3-{[(3-isobutyl-1,2,4-oxadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 983N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-2H-tetraazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-propylisophthalamide 984N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isobutyl-2H-tetraazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 985N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-4-pyridimidinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-propylisophthalamide 986N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isopropyl-4-pyrimidinyl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 987N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethynyl-4-pyrimidinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-di-propylsophthalamide 988N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(6-isopropyl-4-pyrimidinyl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 989N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({[6-(dimethylamino)-4-pyrimidinyl]methyl}amino)-2-hydroxypropyl]-5-meth-yl-N³,N³-dipropylisophthalamide 990N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({[2-(dimethylamino)-4-pyrimidinyl]methyl}amino)-2-hydroxypropyl]-5-methyl-N³,N³-di-propylisophthalamide 991N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({[4-(dimethylamino)-2-pyrimidinyl]methyl}amino)-2-hydroxypropyl]-5-methyl-N³,N³-di-propylisophthalamide 992N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-isopropyl-2-pyrimidinyl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 993N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4-ethyl-2-pyrimidinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide994N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(5-ethyl-3-pyridazinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide995N³-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(dimethylamino)benzyl]amino}-2-hydroxypropyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide996N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-isopropyl-3-pyridazinyl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 997N³-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1-propynyl)benzyl]amino}propyl)-N⁵,N⁵-diproyl-3,5-pyridinedicarboxamide998N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(6-isopropyl-4-pyridazinyl)methyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 999N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide1000N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(6-ethyl-4-pyridazinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide1001N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide1002N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(6-ethyl-2-pyrazinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide1003N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide1004N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(6-isoproyl-2-pyrazinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide1005N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3,4,5-trifluorobenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide1006N¹-((1S,2R)-2-hydroxy-1-(3,4,5-trifluorobenzyl)-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide1007N¹-((1S,2R)-2-hydroxy-1-(2,3,5,6-tetrafluorobenzyl)-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-methyl-N³,N³-di-propylisophthalamide 1008N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2,3,5,6-tetrafluorobenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide1009N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-5-meth-yl-N³,N³-dipropylisophthalamide 1010N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-N³,N³-di-propyl-1,3,5-benzenetricarboxamide 1011N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1R,2S)-6-ethyl-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-2-hydroxypropyl)-5-meth-yl-N³,N³-dipropylisophthalamide 1012N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1R,2S)-6-ethyl-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-2-hydroxypropyl)-N³,N³-di-propyl-1,3,5-benzenetricarboxamide 1013N¹{(1S,2R)-2-hydroxy-1-(1H-indol-5-ylmethyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1014N¹-[(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-(1H-indol-5-ylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide1015N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-methylbenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide1016N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-methylbenzyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1017N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[3-(trifluoromethyl)benzyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide1018N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[3-(trifluoromethyl)benzyl]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1019N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-pyridinylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide1020N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-pyridinylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1021N¹-{(1S,2R)-1-[3-fluoro-5-(trifluoromethyl)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-di-propylisophthalamide 1022N¹-{(1S,2R)-1-[3-fluoro-5-(trifluoromethyl)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-di-propyl-1,3,5-benzenetricarboxamide 1023N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[3-(trifluoromethoxy)benzyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide1024N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[3-(trifluoromethoxy)benzyl]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1025N¹-{(1S,2R)-2-hydroxy-1-(3-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1026N¹-{(1S,2R)-2-hydroxy-1-(3-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1027N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(4-methylbenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide1028N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(4-methylbenzyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1029N¹-{(1S,2R)-1-(4-fluoro-3-methylbenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1030N¹-{(1S,2R)-1-(4-fluoro-3-methylbenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1031N¹-{(1S,2R)-1-(4-chlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1032N¹-{(1S,2R)-1-(4-chlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1033N¹-{(1S,2R)-2-hydroxy-1-(3-methoxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1034N¹-{(1S,2R)-2-hydroxy-1-(3-methoxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1035N¹-{(1S,2R)-2-hydroxy-1-(4-methoxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1036N¹-{(1S,2R)-2-hydroxy-1-(4-methoxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1037N¹-{(1S,2R)-1-(3-chloro-5-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1038N¹-{(1S,2R)-1-(3-chloro-5-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1039N¹-{(1S,2R)-1-(4-chloro-3-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1040N¹-{(1S,2R)-1-(4-chloro-3-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1041N¹-{(1S,2R)-1-(3,5-dichlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1042N¹-{(1S,2R)-1-(3,5-dichlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1043N¹-{(1S,2R)-1-[4-(dimethylamino)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1044N¹-{(1S,2R)-1-[4-(dimethylamino)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1045N¹-{(1S,2R)-1-(3-chlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1046N¹-{(1S,2R)-1-(3-chlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1047N¹-{(1S,2R)-1-(3-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1048N¹-{(1S,2R)-1-(3-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1049N¹-{(1S,2R)-2-hydroxy-1-(4-isopropylbenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1050N¹-{(1S,2R)-2-hydroxy-1-(4-isopropylbenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1051N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[(6-methoxy-2-pyridinyl)methyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide1052N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[(6-methoxy-2-pyridinyl)methyl]propyl}-N³,N³-di-propyl-1,3,5-benzenetricarboxamide 1053N¹-{(1S,2R)-2-hdyroxy-3-[(3-methoxybenzyl)amino]-1-[(5-methyl-2-pyridinyl)methyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide1054N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[(5-methyl-2-pyridinyl)methyl]propyl}-N³,N³-dipropyl-1,3,5-benzene-tricarboxamide 1055N¹-{(1S,2R)-1-(3-fluoro-4-methylbenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1056N¹-{(1S,2R)-1-(3-fluoro-4-methylbenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1057N¹-{(1S,2R)-1-(3-fluoro-4-methoxybenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1058N¹-{(1S,2R)-1-(3-fluoro-4-methoxybenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1059N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-methoxy-5-methylbenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide1060N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-methoxy-5-methylbenzyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1061N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1,3-thiazol-2-ylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide1062N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1,3-thiazol-2-ylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide1063N¹-{(1S,2R)-1-[(5-chloro-2-thienyl)methyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide1064N¹-{(1S,2R)-1-[(5-chloro-2-thienyl)methyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide

Examples 1,065–1,155

Following the general procedure of CHART A and EXAMPLES 4–6, 321–327,329–464, 466–527, 529–579, 597–619 and 633–708 and making non-criticalvariations, and using the appropriate amines (VIII) and amide formingagents (IX), the titled compounds are obtained.

EXAMPLE Substituted Amine (X) 1,065N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(1-pyrrolidinylcarbonyl)benzamide1,066N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-2-[(methylsulfonyl)amino]1,3-thiazole-4-carboxamide 1,067N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide1,068N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(propylsulfonyl)amino]-1,3-thiazole-4-carboxamide1,069N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-3-(1-pyrrolidinylcarbonyl)benzamide1,070N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[(propylsulfonyl)amino]-1,3-thiazole-4-carboxamide1,071N-{(1S,2R)-1-benzy-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide1,072N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,073N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl]amino}-2-hydroxypropyl)-4-hydroxy-3-(1-pyrrolidinylcarbonyl)benzamide 1,074N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl]amino}-2-hydroxypropyl)-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,075N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide1,076N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl]amino}-2-hydroxypropyl)-5-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,077N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-4-hydroxy-3-(1-pyrrolidinylcarbonyl)benzamide 1,078N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,079N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[3-methoxybenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,080N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-5-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,081N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-3-(1-piperidinylcarbonyl)benzamide1,082N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-[(methylsulfonyl)amino]-l,3-oxazole-2-carboxamide1,083N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide1,084N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-4-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide 1,085N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(1-piperidinylcarbonyl)benzamide1,086N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide 1,087N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide1,088N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-4-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide 1,089N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(4-morpholinylcarbonyl)benzamide1,090N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-[(ethylsulfonyl)amino]-1,3-oxazole-2-carboxamide1,091N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-2-[methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,092N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-[(ethylsulfonyl)amino]-1,3-oxazole-2-carboxamide1,093N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(4-morpholinylcarbonyl)benzamide1,094N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-[(propylsulfonyl)amino]-1,3-oxazole-2-carboxamide 1,095N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,096N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-[(methylsulfonyl)amino]-1,3-thiazole-2-carboxamide 1,097N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-3-(1-piperazinylcarbonyl)benzamide1,098N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-[(methylsulfonyl)amino]-1,3-thiazole-2-carboxamide1,099N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,100N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-5-carboxamide1,101N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(1-piperazinylcarbonyl)benzamide1,102N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl]-4-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-5-carboxamide 1,103N⁴-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4,5-dicarboxamide 1,104N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-5-carboxamide 1,105N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-methylisophthalamide1,106N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-5-carboxamide 1,107N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(ethylsulfonyl)amino]-1,3-oxazole-4-carboxamide1,108N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[3-iodobenzyl)amino]propyl}-5-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide1,109 N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-N³-methylisophthalamide 1,110N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-methyl-5-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide 1,111N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[(ethylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,112N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-methyl-5-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide 1,113N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³-ethyl-4-hydroxyisophthalamide1,114N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide 1,115N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(ethylsulfonyl)amino]-1,3-oxazole-4-carboxamide1,116N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(methylsulfonyl)amino]-3-isoxazolecarboxamide1,117N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-4-hydroxyisophthalamide1,118N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-[(methylsulfonyl)amino]-3-isoxazolecarboxamide1,119 N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(propylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,120N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-[(methylsulfonyl)amino]-5-isoxazolecarboxamide1,121N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³-ethyl-4-hydroxyisophthalamide1,122N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(methylsulfonyl)amino]-5-isoxazolecarboxamide1,123N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[(propylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,124N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-(hydroxymethyl)-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,125N³-(cyclopropylmethyl)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-hydroxyisophthalamide 1,1265-cyclopropyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,127N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(propylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,128N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-isopropyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,129N³-(cyclopropylmethyl)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxyisophthalamide 1,130N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isopentylamino)propyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide1,131N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-2-[(propylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,132N-[(1S,2R)-3-(cyclopropylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide1,133N-[(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide1,134N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-isobutylisophthalamide1,1352-{[(cyclopropylmethyl)sulfonyl]amino}-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1,3-oxazole-4-carboxamide 1,136N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-isobutyl-N³-methylisophthalamide 1,137N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(isobutylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,138N3-(cyclopropylmethyl)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-methylisophthalamide 1,139N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[(isobutylsulfonyl)amino]-1,3-1,3-oxazole-4-carboxamide 1,140N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-methyl-N³-propylisophthalamide 1,141N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(isobutylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,142N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-N³-methyl-N³-propylisophthalamide 1,143N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(phenylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,144N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³-ethyl-4-hydroxy-N³-propylisophthalamide 1,145N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-{[(4-methylphenyl)sulfony]amino}-1,3-oxazole-4-carboxamide 1,146N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-4-hydroxy-N³-propylisophthalamide 1,147N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-{[(4-methylphenyl)sulfonyl]amino}-1,3-oxazole-4-carboxamide 1,148N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(phenylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,149N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³,N³- dipropylisophthalamide 1,150N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,151N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-N³,N³- dipropylisophthalamide 1,152N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide 1,153N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-hydroxy-N³,N³- dipropylisophthalamide 1,154N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide 1,155N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide

Examples 1,156–1,214

Following the general procedure of CHART A and EXAMPLES 4–6, 321–327,329–464, 466–527, 529–579, 597–619 and 633–708 and making non-criticalvariations, and using the appropriate amines (VIII) and amide formingagents (IX), the titled compounds are obtained.

EXAMPLE Substituted Amine (X) MH+ 1,156N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-[propionyl(propyl)amino]benzamide532.5 1,157N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-butyl-1H-indole-5-carboxamideAnal. Found C = 73.58; H = 7.44; N = 8.24. 1,159N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[butyl(propionyl)amino]-5-methylbenzamide546.3 1,160N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-1-propyl-1H-indole-6-carboxamide500.3 1,161N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-(1-propylbutyl)-1H-indole-6-carboxamide542.2 1,162N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)methyl]amino}propyl)-5-methyl-573.3 N³,N³-dipropylisophthalamide 1,163N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyb-5-{[(trifluoromethyl)713.0 sulfonyl]amino}isophthalamide 1,1643-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-[(dipropylamino)carbonyl]576.1 benzoic acid 1,165N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-prop-1-604.4 ynylisophthalamide 1,166N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-(dipropylamino)isonicotinamideHRMS [32 505.31 76 1,167N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide 1,168N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(ethylsulfonyl)amino]-N³,N³-dipropylisophthalamide 1,169N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-[(propylsulfonyl)amino]isophthalamide 1,170N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(isopropylsulfonyl)amino]-N³,N³-dipropylisophthalamide 1,171N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(isobutylsulfonyl)amino]-N³,N³-dipropylisophthalamide 1,172N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-[(thien-2-ylsulfonyl)amino]isophthalamide 1,173N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(2-furylsulfonyl)amino]-N³,N³-dipropylisophthalamide 1,174N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-[(1,3-thiazol-5-ylsulfonyl)amino]isophthalamide 1,175N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl-5-}(1,3-oxazol-5-ylsulfonyl)amino]-N³,N³-dipropylisophthalamide 1,176N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(1,3-oxazol-4-ylsulfonyl)amino]-N³,N³dipropylisophthalamide 1,177N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-[(1,3-thiazol-4-ylsulfonyl)amino]isophthalamide 1,178N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-{[(1-methyl-1H-[(1,3-thiazol-4-sulfonyl]amino}-N³,N³-dipropylisophthalamide 1,179N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(1,3-thiazol-4-N³dipropylisophthalamide 1,1805-{[(5-cyanopyridin-2-yl)sulfonyl[amino}-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]2-hydroxypropyl}-N³,N³-dipropylisophthalamide 1,181N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-({[5-(trifluoromethyl)pyridin-2-yl]sulfonyl}amino)isophthalamide 1,182N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}benzamide 1,183N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-({[5-(trifluoromethyl)pyridin-2-yl]sulfonyl}amino)benzamide 1,1843-{[(5-cyanopyridin-2-yl)sulfonyl]amino}-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}benzamide 1,185N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(phenylsulfonyl)amino]benzamide1,186N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3[(methylsulfonyl)amino]benzaamide1,187N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(ethylsulfonyl)amino]benzamide1,188N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(propylsulfonyl)amino]benzamide1,189N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(isobutylsulfonyl)amino]benzamide1,190N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(isopropylsulfonyl)amino]benzamide1,191N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(1-ethylpropyl)sulfonyl]amino}benzamide 1,1923-[(cyclohexylsulfonyl)amino]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}benzamide 1,193N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino)-2-hydroxypropyl}-3-{[(1-propylbutyl)sulfonyl]amino}benzamide 1,194N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(thien-2-ylsulfonyl)amino]benzamide 1,195 N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(2-furylsulfonyl)amino]benzamide 1,196N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(isoxazol-5-ylsulfonyl)amino]benzamide 1,197N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(isoxazol-3-ylsulfonyl)amino]benzamide 1,198N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(3-furylsulfonyl)amino]benzamide1,199 N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(thien-3-ylsulfonyl)amino]benzamide 1,200 N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1,3-thiazol-4-ylsulfonyl)amino]benzamide 1,201N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1,3-thiazol-5-ylsulfonyl)amino]enzamide 1,202N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1,3-thiazol-2-ylsulfonyl)amino]benzamide 1,203N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isopentylamino)propyl]-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide 1,204N¹-[(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide 1,205N¹-[(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-[(methylsulfonyl)amino]-N³,N3-dipropylisoplithalamide 1,206N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isopentylamino)propy]-5-[methylsulfonyl)amino]-N³,N³-dipropylisophthalamide 1,207N¹-(tert-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isophthalamide1,208N¹-(tert-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide 1,2095-bromo-N¹-(tert-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isophthalamide1,2103-tert-butoxy-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}benzamide1,2113-tert-butoxy-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylbenzamide1,212N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(trifluoromethyl)sulfonyl]amino}benzamide 1,213N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(trifluoromethoxy)benzamide1,214N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-methyl-5-(trifluoromethoxy)benzamide

Examples 1,215–1,259

Following the general procedure of CHART A and EXAMPLES 4–6, 321–327,329–464, 466–527, 529–579, 597–619 and 633–708 and making non-criticalvariations, and using the appropriate amines (VIII) and amide formingagents (IX), the titled compounds are obtained.

EXAM- PLE Substituted Amine (X) [M + H]+ 1,215N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3- 581.4iodobenzyl)amino]propyl}-2-hydroxy-2-(4- methylphenyl)acetamide 1,216N1-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- 610.4[(3-iodobenzyl)amino]propyl}-4-hydroxy-N3- methylisophthalamide 1,217N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3- 642.4iodobenzyl)amino]propyl}-2-hydroxy-2-(4-methoxy- 3-nitrophenyl)acetamide1,218 5-(aminosulfonyl)-N-{(1S,2R)-1-(3,5-difluoro- 646.5benzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}- 2-methoxybenzamide1,219 N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3- 650.5iodobenzyl)amino]propyl}-4-hydroxy-3-(pyrrolidin- 1-ylcarbonyl)benzamide1,220 N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3- 621.4iodobenzyl)amino]propyl}-2-[(methyl-sulfonyl)amino]-1,3-oxazole-4-carboxamide 1,221N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- 663.4[(3-methoxybenzyl)amino]propyl}-5-(3,5-dimethyl-isoxazol-4-yl)-N³,N³-dipropylisophthalamide 1,222N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- 651.4[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1,3-thiazol-2-yl)isophthalamide 1,2233-(cyclohexylcarbonyl)-N-{(1S,2R)-1-(3,5- 565.4difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methylbenzamide 1,224N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- 540.4[(3-methoxybenzyl)amino]propyl}-5-methyl-N³- propylisophthalamide 1,2253-[cyclohexyl(hydroxy)methyl]-N-{(1S,2R)-1-(3,5- 567.4difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methylbenzamide 1,226N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 647.5ethylbenzyl)amino]-2-hydroxypropyl}-5-(4-methyl-1,3-oxazol-2-yl)-N³,N³-dipropylisophthalamide 1,227N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 567ethylbenzyl)amino-1-2-hydroxypropyl}-N⁵,N⁵-dipropylpyridine-3,5-dicarboxamide 1,228N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- 600{[(3-isobutyl-1,2,4-oxadiazol-5- yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide 1,229N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 563ethynylbenzyl)amino]-2-hydroxypropyl}-N⁵,N⁵-dipropylpyridine-3,5-dicarboxamide 1,230N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- 581[(3-isopropylbenzyl)amino]propyl}-N⁵,N⁵-dipropyl-pyridine-3,5-dicarboxamide 1,231N¹-[(1S,2R)-3-[(1-acetylpiperidin-4-yl)amino]-1- 587(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide 1,232N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- 618[(3-pent-1-ynylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide 1,233N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- 620{[3-(4-hydroxybut-1-ynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide 1,234N¹-{3-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 593ethylbenzyl)amino]-2-hydroxy- propyl}amino)carbonyl]-5-methylbenzoyl}-L-prolinamide 1,235 N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 538ethylbenzyl)amino]-2-hydroxypropyl}-N³-isopropyl- 5-methylisophthalamide1,236 N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 538ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-N³,5-dimethylisophthalamide 1,237N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 548ethylbenzyl)amino]-2-hydroxypropyl}-N³,5-dimethyl-N³-prop-2-ynylisophthalamide 1,238N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 552ethylbenzyl)amino]-2-hydroxypropyl}-N³-isobutyl- 5-methylisophthalamide1,239 N¹-(sec-butyl)-N₃-{(1S,2R)-1-(3,5-difluorobenzyl)- 5523-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5- methylisophthalamide 1,240N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 552ethylbenzyl)amino]-2-hydroxypropyl}-5- methylisophthalamide 1,241N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 552ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-diethyl-5-methylisophthalamide 1,242N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 552ethylbenzyl)amino]-2-hydroxypropyl}-N³,5-dimethyl-N³-propylisophthalamide 1,243N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 552ethylbenzyl)amino]-2-hydroxypropyl}-N³-isopropyl-N³,5-dimethylisophthalamide 1,244N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 566ethylbenzyl)amino]-2-hydroxypropyl}-N¹,5- dimethylisophthalamide 1,245N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 566ethylbenzyl)amino]-2-hydroxypropyl}-N³-isobutyl-N³,5-dimethylisophthalamide 1,246N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 566ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-5-methyl-N³-propylisophthalamide 1,247N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 566ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-N³-isopropyl-5-methylisophthalamide 1,248N¹,N¹-diallyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)- 5763-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5- methylisophthalamide 1,2493-(azepan-1-ylcarbonyl)-N-{(1S,2R)-1-(3,5- 578difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylbenzamide 1,250N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 580ethylbenzyl)amino)-2-hydroxypropyl}-3-[(4-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide 1,251N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 580ethylbenzyl)amino]-2-hydroxypropyl}-3-[(3-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide 1,252N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 580ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-diisopropyl-5-methylisophthalamide 1,253N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 580ethylbenzyl)amino]-2-hydroxypropyl}-N¹-ethyl-5- methylisophthalamide1,254 N¹-(cyclopropylmethyl)-N³-{(1S,2R)-1-(3,5- 592difluorobenyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N¹-propylisophthalamide 1,2551-{3-[({(1S,2R)-1-(3,5-dlfluorobenzyl)-3-[(3- 593ethylbenzyl)amino]-2-hydroxy- propyl}amino)carbonyl]-5-methylbenzoyl}-D-prolinamide 1,256 N¹-cyclohexyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-592 3-[(3-ethylbenzyl)amino-2-hydroxypropyl}-N¹,5-dimethylisophthalamide 1,257N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- 592{[1-(3-methylphenyl)cyclopropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide 1,258N³-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- 579(1,2,3,4-tetrahydronaphthalen-1-ylamino)propyl]-N⁵,N⁵-diisopropylpyridine-3,5-dicarboxamide 1,259N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- 586.1ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(trifluoromethyl)sulfonyl]amino}benzamide

BIOLOGICAL EXAMPLES Example A

Enzyme Inhibition Assay

The compounds of the invention are analyzed for inhibitory activity byuse of the MBP-C125 assay. This assay determines the relative inhibitionof beta-secretase cleavage of a model APP substrate, MBP-C125SW, by thecompounds assayed as compared with an untreated control. A detaileddescription of the assay parameters can be found, for example, in U.S.Pat. No. 5,942,400. Briefly, the substrate is a fusion peptide formed ofmaltose binding protein (MBP) and the carboxy terminal 125 amino acidsof APP-SW, the Swedish mutation. The beta-secretase enzyme is derivedfrom human brain tissue as described in Sinha et.al, 1999, Nature40:537–540) or recombinantly produced as the full-length enzyme (aminoacids 1–501), and can be prepared, for example, from 293 cellsexpressing the recombinant cDNA, as described in WO00/47618.

Inhibition of the enzyme is analyzed, for example, by immunoassay of theenzyme's cleavage products. One exemplary ELISA uses an anti-MBP captureantibody that is deposited on precoated and blocked 96-well high bindingplates, followed by incubation with diluted enzyme reaction supernatant,incubation with a specific reporter antibody, for example, biotinylatedanti-SW 192 reporter antibody, and further incubation withstreptavidin/alkaline phosphatase. In the assay, cleavage of the intactMBP-C125SW fusion protein results in the generation of a truncatedamino-terminal fragment, exposing a new SW-192 antibody-positive epitopeat the carboxy terminus. Detection is effected by a fluorescentsubstrate signal on cleavage by the phosphatase. ELISA only detectscleavage following Leu 596 at the substrate's APP-SW 751 mutation site.

Specific Assay Procedure:

Compounds are diluted in a 1:1 dilution series to a six-pointconcentration curve (two wells per concentration) in one 96-plate rowper compound tested. Each of the test compounds is prepared in DMSO tomake up a 10 millimolar stock solution. The stock solution is seriallydiluted in DMSO to obtain a final compound concentration of 200micromolar at the high point of a 6-point dilution curve. Ten (10)microliters of each dilution is added to each of two wells on row C of acorresponding V-bottom plate to which 190 microliters of 52 millimolarNaOAc, 7.9% DMSO, pH 4.5 are pre-added. The NaOAc diluted compound plateis spun down to pellet precipitant and 20 microliters/well istransferred to a corresponding flat-bottom plate to which 30 microlitersof ice-cold enzyme-substrate mixture (2.5 microliters MBP-C125SWsubstrate, 0.03 microliters enzyme and 24.5 microliters ice cold 0.09%TX100 per 30 microliters) is added. The final reaction mixture of 200micromolar compound at the highest curve point is in 5% DMSO, 20millimolar NaAc, 0.06% TX100, at pH 4.5.

Warming the plates to 37 degrees C. starts the enzyme reaction. After 90minutes at 37 degrees C., 200 microliters/well cold specimen diluent isadded to stop the reaction and 20 microliters/well is transferred to acorresponding anti-MBP antibody coated ELISA plate for capture,containing 80 microliters/well specimen diluent. This reaction isincubated overnight at 4 degrees C. and the ELISA is developed the nextday after a 2 hours incubation with anti-192SW antibody, followed byStreptavidin-AP conjugate and fluorescent substrate. The signal is readon a fluorescent plate reader.

Relative compound inhibition potency is determined by calculating theconcentration of compound that showed a fifty percent reduction indetected signal (IC₅₀) compared to the enzyme reaction signal in thecontrol wells with no added compound. In this assay, the compounds ofthe invention exhibited an IC₅₀ of less than 50 micromolar.

Example B

Cell Free Inhibition Assay Utilizing a Synthetic APP Substrate

A synthetic APP substrate that can be cleaved by beta-secretase andhaving N-terminal biotin and made fluorescent by the covalent attachmentof oregon green at the Cys residue is used to assay beta-secretaseactivity in the presence or absence of the inhibitory compounds of theinvention. Useful substrates include the following:

-   Biotin-SEVNL-DAEFR[oregon green]KK [SEQ ID NO: 1]-   Biotin-SEVKM-DAEFR[oregon green]KK [SEQ ID NO: 2]-   Biotin-GLNIKTEEISEISY-EVEFRC[oregon green]KK [SEQ ID NO: 3]-   Biotin-ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF[oregon green]KK [SEQ ID NO:4]-   Biotin-FVNQHLCoxGSHLVEALY-LVCoxGERGFFYTPKA[oregon green]KK [SEQ ID    NO: 5]

The enzyme (0.1 nanomolar) and test compounds (0.001–100 micromolar) areincubated in pre-blocked, low affinity, black plates (384 well) at 37degrees C. for 30 minutes. The reaction is initiated by addition of 150millimolar substrate to a final volume of 30 microliter per well. Thefinal assay conditions are: 0.001–100 micromolar compound inhibitor; 0.1molar sodium acetate (pH 4.5); 150 nanomolar substrate; 0.1 nanomolarsoluble beta-secretase; 0.001% Tween 20, and 2% DMSO. The assay mixtureis incubated for 3 hours at 37 degrees C., and the reaction isterminated by the addition of a saturating concentration of immunopurestreptavidin. After incubation with streptavidin at room temperature for15 minutes, fluorescence polarization is measured, for example, using aLJL Acqurest (Ex485 nm/Em530 nm). The activity of the beta-secretaseenzyme is detected by changes in the fluorescence polarization thatoccur when the substrate is cleaved by the enzyme. Incubation in thepresence or absence of compound inhibitor demonstrates specificinhibition of beta-secretase enzymatic cleavage of its synthetic APPsubstrate. In this assay, compounds of the invention exhibited an IC50of less than 50 micromolar.

Example C

Beta-secretase Inhibition: P26-P4′SW Assay

Synthetic substrates containing the beta-secretase cleavage site of APPare used to assay beta-secretase activity, using the methods described,for example, in published PCT application WO/00/47618. The P26-P4′SWsubstrate is a peptide of the sequence:(biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNLDAEF [SEQ ID NO: 6] The P26-PIstandard has the sequence:

-   (biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL [SEQ ID NO: 7]

Briefly, the biotin-coupled synthetic substrates are incubated at aconcentration of from about 0 to about 200 micromolar in this assay.When testing inhibitory compounds, a substrate concentration of about1.0 micromolar is preferred. Test compounds diluted in DMSO are added tothe reaction mixture, with a final DMSO concentration of 5%. Controlsalso contain a final DMSO concentration of 5%. The concentration of betasecretase enzyme in the reaction is varied, to give productconcentrations with the linear range of the ELISA assay, about 125 to2000 picomolar, after dilution.

The reaction mixture also includes 20 millimolar sodium acetate, pH 4.5,0.06% Triton X100, and is incubated at 37 degrees C. for about 1 to 3hours. Samples are then diluted in assay buffer (for example, 145.4nanomolar sodium chloride, 9.51 millimolar sodium phosphate, 7.7millimolar sodium azide, 0.05% Triton X405, 6g/liter bovine serumalbumin, pH 7.4) to quench the reaction, then diluted further forimmunoassay of the cleavage products.

Cleavage products can be assayed by ELISA. Diluted samples and standardsare incubated in assay plates coated with capture antibody, for example,SW192, for about 24 hours at 4 degrees C. After washing in TTBS buffer(150 millimolar sodium chloride, 25 millimolar Tris, 0.05% Tween 20, pH7.5), the samples are incubated with strepavidin-AP according to themanufacturer's instructions. After a one hour incubation at roomtemperature, the samples are washed in TTBS and incubated withfluorescent substrate solution A (31.2 g/liter2-amino-2-methyl-1-propanol, 30 mg/liter, pH 9.5). Reaction withstreptavidin-alkaline phosphate permits detection by fluorescence.Compounds that are effective inhibitors of beta-secretase activitydemonstrate reduced cleavage of the substrate as compared to a control.

Example D

Assays Using Synthetic Oligopeptide-Substrates

Synthetic oligopeptides are prepared that incorporate the known cleavagesite of beta-secretase, and optionally detectable tags, such asfluorescent or chouromogenic moieties. Examples of such peptides, aswell as their production and detection methods are described in U.S.Pat. No. 5,942,400, herein incorporated by reference. Cleavage productscan be detected using high performance liquid chromatography, orfluorescent or chromogenic detection methods appropriate to the peptideto be detected, according to methods well known in the art. By way ofexample, one such peptide has the sequence SEVNL-DAEF [SEQ ID NO: 8],and the cleavage site is between residues 5 and 6. Another preferredsubstrate has the sequence ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF [SEQ ID NO:9], and the cleavage site is between residues 26 and 27.

These synthetic APP substrates are incubated in the presence ofbeta-secretase under conditions sufficient to result in beta-secretasemediated cleavage of the substrate. Comparison of the cleavage resultsin the presence of the compound inhibitor to control results provides ameasure of the compound's inhibitory activity.

Example E

Inhibition of Beta-secretase Activity—Cellular Assay

An exemplary assay for the analysis of inhibition of beta-secretaseactivity utilizes the human embryonic kidney cell line HEKp293 (ATCCAccession No. CRL-1573) transfected with APP751 containing the naturallyoccurring double mutation Lys651Met52 to Asn651Leu652 (numbered forAPP751), commonly called the Swedish mutation and shown to overproduce Abeta (Citron et.al., 1992, Nature 360:672–674), as described in U.S.Pat. No. 5,604,102.

The cells are incubated in the presence/absence of the inhibitorycompound (diluted in DMSO) at the desired concentration, generally up to10 micrograms/ml. At the end of the treatment period, conditioned mediais analyzed for beta-secretase activity, for example, by analysis ofcleavage fragments. A beta can be analyzed by immunoassay, usingspecific detection antibodies. The enzymatic activity is measured in thepresence and absence of the compound inhibitors to demonstrate specificinhibition of beta-secretase mediated cleavage of APP substrate.

Example F

Inhibition of Beta-Secretase in Animal Models of AD

Various animal models can be used to screen for inhibition ofbeta-secretase activity. Examples of animal models useful in theinvention include, but are not limited to, mouse, guinea pig, dog, andthe like. The animals used can be wild type, transgenic, or knockoutmodels. In addition, mammalian models can express mutations in APP, suchas APP695-SW and the like described herein. Examples of transgenicnon-human mammalian models are described in U.S. Pat. Nos. 5,604,102,5,912,410 and 5,811,633.

PDAPP mice, prepared as described in Games et.al., 1995, Nature373:523–527 are useful to analyze in vivo suppression of A beta releasein the presence of putative inhibitory compounds. As described in U.S.Pat. No. 6,191,166, 4 month old PDAPP mice are administered compoundformulated in vehicle, such as corn oil. The mice are dosed withcompound (1–30 mg/ml; preferably 1–10 mg/ml). After time, e.g., 3–10hours, the animals are sacrificed, and brains removed for analysis.

Transgenic animals are administered an amount of the compound inhibitorformulated in a carrier suitable for the chosen mode of administration.Control animals are untreated, treated with vehicle, or treated with aninactive compound. Administration can be acute, i.e., single dose ormultiple doses in one day, or can be chronic, i.e., dosing is repeateddaily for a period of days. Beginning at time 0, brain tissue orcerebral fluid is obtained from selected animals and analyzed for thepresence of APP cleavage peptides, including A beta, for example, byimmunoassay using specific antibodies for A beta detection. At the endof the test period, animals are sacrificed and brain tissue or cerebralfluid is analyzed for the presence of A beta and/or beta-amyloidplaques. The tissue is also analyzed for necrosis.

Animals administered the compound inhibitors of the invention areexpected to demonstrate reduced A beta in brain tissues or cerebralfluids and reduced beta amyloid plaques in brain tissue, as comparedwith non-treated controls.

Example G

Inhibition of A Beta Production in Human Patients

Patients suffering from Alzheimer's Disease (AD) demonstrate anincreased amount of A beta in the brain. AD patients are administered anamount of the compound inhibitor formulated in a carrier suitable forthe chosen mode of administration. Administration is repeated daily forthe duration of the test period. Beginning on day 0, cognitive andmemory tests are performed, for example, once per month.

Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; A beta depositsin the brain; amyloid plaque in the brain; and scores for cognitive andmemory function, as compared with control, non-treated patients.

Example H

Prevention of A Beta Production in Patients at Risk for AD

Patients predisposed or at risk for developing AD are identified eitherby recognition of a familial inheritance pattern, for example, presenceof the Swedish Mutation, and/or by monitoring diagnostic parameters.Patients identified as predisposed or at risk for developing AD areadministered an amount of the compound inhibitor formulated in a carriersuitable for the chosen mode of administration. Administration isrepeated daily for the duration of the test period. Beginning on day 0,cognitive and memory tests are performed, for example, once per month.

Patients administered the compound inhibitors are expected todemonstrate slowing or stabilization of disease progression as analyzedby changes in one or more of the following disease parameters: A betapresent in CSF or plasma; brain or hippocampal volume; amyloid plaque inthe brain; and scores for cognitive and memory function, as comparedwith control, non-treated patients.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereby and should only be construed by interpretation ofthe scope of the appended claims.

1. A substituted amine of formula (X)

where R₁ is: —(CH₂)_(n1)—(R_(1-aryl)) where n₁ is one and whereR_(1-aryl) is phenyl optionally substituted with one, two, three, orfour of the following substituents on the aryl ring: (A) C₁–C₆ alkyloptionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, —C≡N,—CF₃, C₁–C₃ alkoxy, (B) C₂–C₆ alkenyl with one or two double bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, (C)C₂–C₆ alkynyl with one or two triple bonds, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, (D) —F, Cl, —Br or —I, (F)—C₁–C₆ alkoxy optionally substituted with one, two, or three of: —F, (G)—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined below, (H)—OH, (I) —C≡N, (J) C₃–C₇ cycloalkyl, optionally substituted with one,two or three substituents selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a)and R_(1-b) are —H or C₁–C₆ alkyl, (K) —CO—(C₁–C₄ alkyl), (L)—SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (M)—CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, or(N) —SO₂—(C₁–C₄ alkyl), where R₂ is: (I) —H, (II) C₁–C₆ alkyl,optionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areas defined above, (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) orR_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as definedabove; (IV) C₂–C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, (V) C₂–C₆ alkynyl with one ortwo triple bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are —H or C₁–C₆ alkyl, or (VI) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl; whereR₃ is: (I) —H, (II) C₁–C₆ alkyl, optionally substituted with one, two orthree substituents selected from the group consisting of C₁–C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (III)—(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or R_(1-heteroaryl) whereR_(1-aryl) and R_(1-heteroaryl) are as defined above; (IV) C₂–C₆ alkenylwith one or two double bonds, (V) C₂–C₆ alkynyl with one or two triplebonds, or (VI) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,  and where R₂ and R₃ aretaken together with the carbon to which they are attached to form acarbocycle of three, four, five, six or seven carbon atoms, optionallywhere one carbon atom is replaced by a heteroatom selected from thegroup consisting of —O—, —S—, —SO₂—, and —NR_(N-2)—, where R_(N-2) is asdefined below; where R_(N) is: (I) R_(N-1)—X_(N)— where X_(N) is —CO—where R_(N-1) is selected from the group consisting of: (A) R_(N-aryl)where R_(N-aryl) is phenyl optionally substituted with one, two or threeof the following substituents which can be the same or different andare: (1) C₁–C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁–C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above, (2) —OH, (3) —NO₂, (4) —F,—Cl, —Br, or —I, (5) —CO—OH, (6) —C≡N, (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same or different and are selectedfrom the group consisting of: (a) —H, (b) —C₁–C₆ alkyl optionallysubstituted with one substituent selected from the group consisting of:(i) —OH, and (ii) —NH₂, (c) —C₁–C₆ alkyl optionally substituted with oneto three —F, —Cl, —Br, or —I, (d) —C₃–C₇ cycloalkyl, (e) —(C₁–C₂alkyl)—(C₃–C₇ cycloalkyl), (f) —(C₁–C₆ alkyl)—O—(C₁–C₃ alkyl), (g)—C₂–C₆ alkenyl with one or two double bonds, (h) —C₂–C₆ alkynyl with oneor two triple bonds, (i) —C₁–C₆ alkyl chain with one double bond and onetriple bond, (j) —R_(1-aryl) where R_(1-aryl) is as defined above, and(k) R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above, (8)—(CH₂)₀₋₄—CO—(C₁–C₁₂ alkyl), (9) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkenyl with one,two or three double bonds), (10) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkynyl with one,two or three triple bonds), (11) —(CH₂)₀₋₄—CO—(C₃–C₇ cycloalkyl), (12)—(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as defined above, (13)—(CH₂)₀₋₄—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as definedabove, (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) where R_(1-heterocycle) is asdefined above, (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected fromthe group consisting of morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinylwhere each group is optionally substituted with one, two, three, or fourof: C₁–C₆ alkyl, (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selectedfrom the group consisting of: (a) C₁–C₆ alkyl, (b)—(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above, (c) C₂–C₆alkenyl containing one or two double bonds, (d) C₂–C₆ alkynyl containingone or two triple bonds, (e) C₃–C₇ cycloalkyl, and (f)—(CH₂)₀₋₂—(R_(1-heteroaryl)) where R_(1-heteroaryl) is as defined above,(17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are asdefined above, (18) —(CH₂)₀₋₄—SO—(C₁–C₈ alkyl), (19)—(CH₂)₀₋₄—SO₂—(C₁–C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂—(C₃–C₇ cycloalkyl),(21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can be thesame or different and is as defined above, (22) —(CH₂)₀₋₄—N(H orR_(N-5))—CO—N(R_(N-5))₂, where R_(N-5) can be the same or different andis as defined above, (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) canbe the same or different and is as defined above, (24) —(CH₂)₀₋₄—N(—H orR_(N-5))—CO—R_(N-2) where R_(N-5) and R_(N-2) can be the same ordifferent and are as defined above, (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) whereR_(N-2) and R_(N-3) can be the same or different and are as definedabove, (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above, (27)—(CH₂)₀₋₄—O—CO—(C₁–C₆ alkyl), (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂where R_(N-aryl-1) is —H or C₁–C₄ alkyl, (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂where R_(N-5) is as defined above, (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂ whereR_(N-5) is as defined above, (31) —(CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5)is as defined above, (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) isas defined above, (33) —(CH₂)₀₋₄—S—(R_(N-5))₂ where R_(N-5) is asdefined above, (34) —(CH₂)₀₋₄—O—(C₁–C₆ alkyl optionally substituted withone, two, three, four, or five —F), (35) C₃–C₇ cycloalkyl, (36) C₂–C₆alkenyl with one or two double bonds optionally substituted with C₁–C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (37)C₂–C₆ alkynyl with one or two triple bonds optionally substituted withC₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (38)—(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5) and R_(N-2) can bethe same or different and are as described above, or (39)—(CH₂)₀₋₄—C₃–C₇ cycloalkyl, where R_(C) is: (I) —C₁–C₁₀ alkyl optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, —OC═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, —S(═O)₀₋₂ R_(1-a) where R_(1-a) is as defined above,—NR_(1-a)C═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, —C═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, and —S(═O)₂NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (II) —(CH₂)₀₋₃—(C₃–C₈) cycloalkyl where cycloalkyl can beoptionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁–C₆ alkoxy, —O-phenyl, —CO—OH, —CO—O—(C₁–C₄ alkyl), andNR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (III)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) where R_(C-x) and R_(C-y) are —H, C₁–C₄alkyl optionally substituted with one or two —OH, C₁–C₄ alkoxyoptionally substituted with one, two, or three of: —F, —(CH₂)₀₋₄—C₃–C₇cycloalkyl, C₂–C₆ alkenyl containing one or two double bonds, C₂–C₆alkynyl containing one or two triple bonds, phenyl-, and where R_(C-x)and R_(C-y) are taken together with the carbon to which they areattached to form a carbocycle of three, four, five, six, or seven carbonatoms, optionally where one carbon atom is replaced by a heteroatomselected from the group consisting of —O—, —S—, —SO₂—, and —NR_(N-2)—and R_(C-aryl) is the same as R_(N-aryl); (IV)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl) where R_(C-heteroaryl) is thesame as R_(N-heteroaryl) and R_(C-x) and R_(C-y) are as defined above,(V) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-aryl) where R_(C-aryl),R_(C-x) and R_(C-y) are as defined above, (VI)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-heteroaryl) where R_(C-aryl),R_(C-heteroaryl), R_(C-x) and R_(C-y) are as defined above, (VII)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-aryl) whereR_(C-heteroaryl), R_(C-aryl), R_(C-x) and R_(C-y) are as defined above,(VIII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-heteroaryl) whereR_(C-heteroaryl), R_(C-x) and R_(C-y) are as defined above, (IX)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-heterocycle) where R_(C-aryl),R_(C-x) and R_(C-y) are as defined above, and R_(C-heterocycle) is thesame as R_(N-heterocycle), (X)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-heterocycle) whereR_(C-heteroaryl), R_(C-heterocycle), R_(C-x) and R_(C-y) are as definedabove, (XI) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-aryl) whereR_(C-heterocycle), R_(C-aryl), R_(C-x) and R_(C-y) are as defined above,(XII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-heteroaryl) whereR_(C-heterocycle), R_(C-heteroaryl), R_(C-x) and R_(C-y) are as definedabove, (XIII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-heterocycle)where R_(C-heterocycle), R_(C-x) and R_(C-y) are as defined above, (XIV)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle) where R_(C-heterocycle), R_(C-x)and R_(C-y) are as defined above, (XV)—[C(R_(C-1))(R_(C-2))]₁₋₃—CO—N(R_(C-3))₂ where R_(C-1) and R_(C-2) arethe same or different and are selected from the group consisting of: (A)—H, (B) —C₁–C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁–C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O— phenyl, andNR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (C)C₂–C₆ alkenyl with one or two double bonds, optionally substituted withone, two or three substituents selected from the group consisting ofC₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O—phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (D) C₂–C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areas defined above, (E) —(CH₂)₁₋₂—S(O)₀₋₂—(C₁–C₆ alkyl), (F)—(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of C₁–C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O— phenyl,—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (G)—(C₁–C₄ alkyl)—R_(C′-aryl) where R_(C′-aryl) is as defined forR_(1-aryl), (H) —(C₁–C₄ alkyl)—R_(C-heteroaryl) where R_(C-heteroaryl)is as defined above, (I) —(C₁–C₄ alkyl)—R_(C-heterocycle) whereR_(C-heterocycle) is as defined above, (J) —R_(C-heteroaryl) whereR_(C-heteroaryl) is as defined above, (K) —R_(C-heterocycle) whereR_(C-heterocycle) is as defined above, (M)—(CH₂)₁₋₄—R_(C-4)—(CH₂)₀₋₄—R_(C′-aryl) where R_(C-4) is —O—, —S— or—NR_(C-5)— where R_(C-5) is C₁–C₆ alkyl, and where R_(C′-aryl) is asdefined above, (N) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₀₋₄—R_(C-heteroaryl) whereR_(C-4) and R_(C-heteroaryl) are as defined above, and (O) —R_(C′-aryl)where R_(C′-aryl) is as defined above, and where R_(C-3) is the same ordifferent and is: (A) —H, (B) —C₁–C₆ alkyl optionally substituted withone, two or three substituents selected from the group consisting ofC₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O—phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (C) C₂–C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areas defined above, (D) C₂–C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁–C₆ alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, (E) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areas defined above, (F) —R_(C′-aryl) where R_(C′-aryl) is as definedabove, (G) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above,(H) —R_(C-heterocycle) where R_(C-heterocycle) is as defined above, (I)—(C₁–C₄ alkyl)—R_(C′-aryl) where R_(C′-aryl) is as defined above, (J)—(C₁–C₄ alkyl)—R_(C-heteroaryl) where R_(C-heteroaryl) is as definedabove, or (K) —(C₁–C₄ alkyl)—R_(C-heterocycle) where R_(C-heterocycle)is as defined above, (XVI) —CH(R_(C-aryl))₂ where R_(C-aryl) are thesame or different and are as defined above, (XVII)—CH(R_(C-heteroaryl))₂ where R_(C-heteroaryl) are the same or differentand are as defined above, (XVIII) —CH(R_(C-aryl))(R_(C-heteroaryl))where R_(C-aryl) and R_(C-heteroaryl) are as defined above, (XIX)-cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to R_(C-aryl) orR_(C-heteroaryl) or R_(C-heterocycle) where R_(C-aryl) orR_(C-heteroaryl) or R_(C-heterocycle) are as defined above where onecarbon of cyclopentyl, cyclohexyl, or -cycloheptyl is optionallyreplaced with NH, NR_(N-5), O, or S(═O)₀₋₂, and where cyclopentyl,cyclohexyl, or -cycloheptyl can be optionally substituted with one ortwo —C₁–C₃ alkyl, —F, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, ═O, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (XX)C₂–C₁₀ alkenyl containing one or two double bonds optionally substitutedwith one, two or three substituents selected from the group consistingof C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy,—O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (XXI) C₂–C₁₀ alkynyl containing one or two triple bondsoptionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁–C₆ alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, (XXI)—(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁—R_(C-aryl) where R_(C-aryl) is as definedabove and R_(C-6) is —(CH₂)₀₋₆—OH, (XXII)—(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁—R_(C-heteroaryl) where R_(C-heteroaryl) andR_(C-6) is as defined above, (XXIII) —CH(—R_(C-aryl) orR_(C-heteroaryl))—CO—O(C₁–C₄ alkyl) where R_(C-aryl) andR_(C-heteroaryl) are as defined above, (XXIV)—CH(—CH₂—OH)—CH(—OH)-phenyl-NO₂, (XXV) (C₁–C₆ alkyl)—O—(C₁–C₆ alkyl)—OH,(XXVII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂, (XXVIII) —H, or (XXIX)—(CH₂)₀₋₆—C(═NR_(1-a))(NR_(1-a)R_(1-b)) where R_(1-a) and R_(1-b) are asdefined above; or a pharmaceutically acceptable salt thereof.
 2. Asubstituted amine of formula (X) according to claim 1 where R₁ is:—(CH₂)₀₋₁—(R_(1-aryl)) where R_(N) is: R_(N-1)—X_(N)— where X_(N) is—CO—; where R_(N-1) is —R_(N-aryl), and; where R_(C) is: —C₁–C₈ alkyl,—(CH₂)₀₋₃—(C₃–C₇) cycloalkyl, —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl),—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl),—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle), or -cyclopentyl or -cyclohexylring fused to R_(C-aryl) or R_(C-heteroaryl) or R_(C-heterocycle).
 3. Asubstituted amine of formula (X) according to claim 2 where R₂ is —H;where R₃ is —H; where R_(C) is: —(CH₂)₀₋₃—(C₃–C₇) cycloalkyl,—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl),—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl),—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle), or -cyclopentyl or -cyclohexylring fused to a R_(C-aryl) or R_(C-heteroaryl) or R_(C-heterocycle). 4.A substituted amine of formula (X) according to claim 3 where R_(C) is:—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl),—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl), -cyclopentyl or -cyclohexyl ringfused to a R_(C-aryl) or R_(C-heteroaryl) or R_(C-heterocycle).
 5. Asubstituted amine of formula (X) according to claim 1 where R₁ is—(CH₂)—(R_(1-aryl)) where R_(1-aryl) is phenyl.
 6. A substituted amineof formula (X) according to claim 1 where R₁ is —(CH₂)—(R_(1-aryl))where R_(1-aryl) is phenyl substituted with two —F.
 7. A substitutedamine of formula (X) according to claim 6 where the —F substitution is3,5-difluorobenzyl.
 8. A substituted amine of formula (X) according toclaim 1 where R₂ is —H.
 9. A substituted amine of formula (X) accordingto claim 1 where R₃ is —H.
 10. A substituted amine of formula (X)according to claim 1 where R_(N) is R_(N-1)X_(N)— where X_(N) is —CO—,where R_(N-1) is R_(N-aryl) where R_(N-aryl) is phenyl substituted withone —CO—NR_(N-2)R_(N-3) where the substitution on phenyl is 1,3-.
 11. Asubstituted amine of formula (X) according to claim 10 where R_(N-2) andR_(N-3) are the same and are C₃ alkyl.
 12. A substituted amine offormula (X) according to claim 1 where R_(N) is R_(N-1)—X_(N)— whereX_(N) is —CO—, where R_(N-1) is R_(N-aryl) where R_(N-aryl) is phenylsubstituted with one C₁ alkyl and with one —CO—NR_(N-2)R_(N-3) where thesubstitution on the phenyl is 1,3,5-.
 13. A substituted amine of formula(X) according to claim 12 where R_(N-2) and R_(N-3) are the same and areC₃ alkyl.
 14. A substituted amine of formula (X) according to claim 1where R_(C) is: —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) where R_(C-aryl) isphenyl, —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl), -cyclopentyl or-cyclohexyl ring fused to a R_(C-aryl) or R_(C-heteroaryl) orR_(C-heterocycle).
 15. A substituted amine of formula (X) according toclaim 14 where R_(C) is: —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) whereR_(C-aryl) is phenyl.
 16. A substituted amine of formula (X) accordingto claim 15 where phenyl is substituted in the 3-position or3,5-positions.
 17. A substituted amine of formula (X) according to claim14 where R_(C) is: —(CH₂)—R_(C-heteroaryl).
 18. A substituted amine offormula (X) according to claim 14 where R_(C) is:—(CH₂)—R_(C-heterocycle).
 19. A substituted amine of formula (X)according to claim 14 where R_(C) is: -cyclohexyl ring fused to a phenylring.
 20. A substituted amine of formula (X) according to claim 1 wherethe pharmaceutically acceptable salt is selected from the groupconsisting of salts of the following acids acetic, aspartic,benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric,calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic,edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic,glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic,hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic,lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic,methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic,p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogenphosphoric, dihydrogen phosphoric, phthalic, polygalactouronic,propionic, salicylic, stearic, succinic, sulfamic, sulfanilic, sulfonic,sulfuric, tannic, tartaric, teoclic and toluenesulfonic.
 21. Asubstituted amine of formula (X) according to claim 1 which is selectedfrom the group consisting of:N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-furylmethyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(ethylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(benzylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(isopropylamino)propyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(4-toluidino)propyl]-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(4-methoxyphenyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,ethyl{[(3S)-3-({3-[(dipropylamino)carbonyl]benzoyl}amino)-2-hydroxy-4-phenylbutyl]amino}(phenyl)acetate,N¹-((1S)-1-benzyl-2-hydroxy-3-{[(1S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2-chlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(4-chlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(2-hydroxyethoxy)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(2,3-dihydro-1H-inden-1-ylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-hydroxypropyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(tetrahydro-2-furanylmethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,2-diethoxyethyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(butylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(cyclohexylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-pyridinylmethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-3-[(2-aminobenzyl)amino]-1-benzyl-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-pyridinylmethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(1-pyrrolidinyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-hydroxy-2-phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-butoxypropyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-isopropoxypropyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(isopentylamino)propyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-phenylpropyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-methoxyethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-phenoxyethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-propoxyethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,3-dimethylbutyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-phenylbutyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-benzyl-2-hydroxy-3-[(4-nitrobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-chlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(4-chlorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(2-pyridinyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-pyridinylmethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,3-dimethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(trifluoromethoxy)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2-chloro-6-phenoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[4-(trifluoromethyl)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,3-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,5-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,5-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[4-(trifluoromethoxy)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-1-benzyl-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-methylbenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3,4,5-trimethoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethoxy)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,4-dimethoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[([1,1′-biphenyl]-3-ylmethyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,4-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2-fluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-methylbenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-1-phenylethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-1-phenylethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3,5-bis(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(trifluoromethyl)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-1-(1-naphthyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-1-(1-naphthyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-hydroxy-3-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,4-dihydroxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-benzyl-2-hydroxy-3-[(3-methoxypropyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-2-hydroxy-1-methylethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-2-hydroxy-1-methylethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(2-propynylamino)propyl]-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(2-fluorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(3-fluorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(4-fluorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(4-bromophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S)-1-benzyl-2-hydroxy-3-{[2-(3-methoxyphenyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(2,4-dichlorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(3-chlorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S)-1-benzyl-3-{[2-(2,5-dimethoxyphenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(4-methylphenyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[(1R)-1-benzyl-2-hydroxyethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(4-morpholinyl)propyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propyl]-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(4-morpholinyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-hydroxybutyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(2-thienyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-hydroxybutyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-2-hydroxy-1-phenylethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,4-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-2-hydroxy-1-phenylethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(4-tert-butylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(1-phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,4-dimethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino)-1-methyl-2-oxoethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(isobutylamino)-1-methyl-2-oxoethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N³-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(isobutylamino)-1-methyl-2-oxoethyl]amino}propyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino)-1,1-dimethyl-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino)-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(isobutylamino)carbonyl]propyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1R)-1-[(isobutylamino)carbonyl]propyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(ethylamino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isobutylamino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(isobutylamino)-2-methyl-3-oxopropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[4-(dimethylamino)benzyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1S)-1-benzyl-2-(isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(isobutylamino)carbonyl]-2-methylpropyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[2-(dimethylamino)ethyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-pyridinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1S)-1-[(benzyloxy)methyl]-2-(isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1R)-1-[(isobutylamino)carbonyl]-2-methylpropyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(isobutylamino)carbonyl]butyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-1-(hydroxymethyl)-2-(isobutylamino)-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenylethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-1-phenylpropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-2-(ethylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(isobutylamino)-2-oxo-1-phenylethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isopentylamino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(cyclohexylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(butylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxypropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-hydroxy-2-phenylethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3R,5S)-3,5-dimethoxycyclohexyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,dimethyl(1R,3S)-5-{[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}-1,3-cyclohexanedicarboxylate,(1R,3S)-5-{[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}-1,3-cyclohexanedicarboxylicacid,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R)-1-phenylpropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-chlorobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(2-propylpentyl)sulfonyl]benzamide,N¹-[(1S,2R)-3-[([1,1′-biphenyl]-3-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenylpropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1,3-thiazol-5-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-thienylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-pyrazinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,5-difluorobenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-3-[(1,3-benzodioxol-5-ylmethyl)amino]-1-benzyl-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethoxy)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-fluorobenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-methyl-2-furyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(1,2,3,4-tetrahydro-1-naphthalenylamino)propyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methoxy-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-chloro-N³,N³-dipropylisophthalamide,N³-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-fluoro-N³,N³-dipropylisophthalamide,N²-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N⁵,N⁵-dipropyl-2,5-thiophenedicarboxamide,N⁴-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N²,N²-dipropyl-2,4-pyridinedicarboxamide,N⁴-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N⁶,N⁶dipropyl-4,6-pyrimidinedicarboxamide,N-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-3-(4-morpholinylcarbonyl)benzamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide,N¹-[(1S,2R)-3-{[(1R)-1-[(benzyloxy)methyl]-2-(isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R)-1-(hydroxymethyl)-2-(isobutylamino)-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(pentylamino)propyl]-N³,N³-dipropylisophthalamide,N¹-[(1S)-3-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-1-benzyl-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1,3-thiazol-5-ylmethyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,3-benzoyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}[1,1′-biphenyl]-3-carboxamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³-(2-methoxyethyl)-N³-propylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-ethoxybenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-naphthamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1R)-1,2,3,4-tetrahydro-1-naphthalenylamino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1R)-3-{[3,5-bis(trifluoromethyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-fluoro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,3-difluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3-fluoro-4-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,5-difluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3-fluoro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,4-difluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[4-fluoro-3-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-chloro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[4-chloro-3-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(2,3-dihydro-1H-inden-2-ylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-benzyl-2-hydroxy-3-[(3-nitrobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3-(difluoromethoxy)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-ethoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(5-methyl-2-pyrazinyl)methyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-bromo-4-fluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,5-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethoxybenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isobutoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-methyl-1,3-thiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³-methyl-N³-propylisophthalamide,N²-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N⁵,N⁵-dipropyl-2,5-furandicarboxamide,N³-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-[(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(1,2-diphenylethyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,isomer A,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,isomer B,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(dimethylamino)benzamide,N-[(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl]-2-methyl-1H-benzimidazole-5-carboxamide,3-(aminosulfonyl)-N-{(1S)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-chlorobenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-cyanobenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-chloro-3-nitrobenzamide,methyl3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-nitrobenzoate,tert-butyl3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]phenylcarbamate,N-[(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl]-9,10-dioxo-9,10-dihydro-2-anthrancenylcarboxamide,N-[(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl]-1H-1,2,3-benzotriazole-6-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1H-indole-5-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-fluoro-5-(trifluoromethyl)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(trifluoromethyl)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-(butylamino)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(trifluoromethoxy)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3,5-dimethoxybenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3,5-dimethylbenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3,5-difluorobenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3,5-dichlorobenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-(benzyloxy)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1,3-benzodioxole-5-carboxamide,3-(acetylamino)-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}benzamide,4-(acetylamino)-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}benzamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3,5-dimethyl-4-isoxazolyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-phenylpropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-furylmethyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(tetrahydro-3-furanylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-propoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-pyridinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-hydroxy-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-methyl-1-(3-methylphenyl)ethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylamino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2,5-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[2-chloro-5-(trifluoromethyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-hydroxy-5-methylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,5-chloro-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(1-benzofuran-2-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1R)-1-(3-bromophenyl)ethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[butyl(butyryl)amino]-5-methylbenzamide,N¹-{1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide,N³-{1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N¹,N¹-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-butyl-1H-indole-6-carboxamide,N¹-[(1S,2R)-3-anilino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,5-bromo-N¹-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-methylpentanamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-methylpentanamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-hydroxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-cyano-N³,N³-dipropylisophthalamidehydrochloride,N^(l)-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,1-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-oxo-5-(1-piperidinyl)pentanamidetrifluroacetate,5-(aminosulfonyl)-N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1-pyrrolidinylsulfonyl)isophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylamino)sulfonyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(dimethylamino)sulfonyl]-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-methyl-3-(methylsulfonyl)propanamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(methylsulfonyl)propanamide,2-amino-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1,3-thiazole-4-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(methylsulfonyl)pentanamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁴-phenylsuccinamide,(3R)-N⁴-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2,2,3-trimethylbutanediamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(dipropylamino)sulfonyl]propanamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl)}-4-oxo-4-(1-piperidinyl)butanamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁴,N⁴-dipropylsuccinamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-oxo-5-(1-piperidinyl)pentanamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵-phenylpentanediamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3,3-dimethyl-4-oxo-4-(1-piperidinyl)butanamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-(isopentylsulfonyl)butanamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2,2-dimethyl-N⁴,N⁴-dipropylsuccinamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-[(dipropylamino)sulfonyl]butanamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-[(methylanilino)sulfonyl]butanamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(methylanilino)sulfonyl]propanamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}acetamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(isopentylsulfonyl)propanamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-oxo-5-(1-piperidinyl)pentanamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-oxo-5-(1-piperidinyl)pentanamideandN-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-[(dipropylamino)sulfonyl]propanamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-ethyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-isobutyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-tert-butyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-cyano-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dimethyl-N⁵,N⁵-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-amino-1-benzyl-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(isopentylamino)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³-propyl-1,3,5-benzenetricarboxamide,N-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[butyryl(propyl)amino]-5-methylbenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-propyl-1H-indole-6-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-propyl-1H-indole-6-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,4-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-aminobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}octanamide,N³-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}amino)propyl]-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-methylbenzamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(1H-isoindol-3-ylamino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹,N¹-diallyl-5-chloro-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}isophthalamide,N¹,N¹-diallyl-5-chloro-N³{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}isophthalamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopentyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-{((1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(dimethylamino)benzyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-[(4,5-dimethyl-2-furyl)methyl]amino}-2-hydpropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopentyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(cyclopropylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(cyclopropylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-furylmethyl)amino]-2-hydroxypropyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(tetrahydro-2-furanylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopropyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-oxo-3-azepanyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-methyl-2-furyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2S)-tetrahydro-2-furanylmethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,5-chloro-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N³,N³-di(2-propynyl)isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropenylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-propoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(hexylamino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzamide,methyl4-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)benzoate,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-isoxazolylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,(1R,2R)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N²,N²-dipropyl-1,2-cyclopropanedicarboxamide,N³-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2S)-tetrahydro-2-furanylmethyl]amino}propyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,4-(butyrylamino)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}benzamide,N¹-[(1S,2R)-3-[(3-amino-3-oxopropyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N³-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide1-oxide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-oxabicyclo[2.2.1]hept-2-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-methyl-1,3-thiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-1,3-thiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3R)-2-oxoazepanyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(cyclobutylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(butylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(5-hexynylamino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N³-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-methyl-2-furyl)methyl]amino}propyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(2-furyl)-1-methylethyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-5-isoxazolyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isobutyl-1,3-thiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(dipropylamino)sulfonyl]propanamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(2-chlorophenyl)ethyl]amino}-2-hydroxypropyl)-N³N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(2-oxo-1-pyrrolidinyl)propyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(cyclohexylmethyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(cyclopropylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-oxo-3-azepanyl)amino]propyl}-N³,N³-dipropylisophthalamide,N-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-3-(butylsulfonyl)benzamide,N¹-[(1S,2R)-1-benzyl-3-({2-[(2-ethylhexyl)oxy]ethyl}amino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[1-(4-hydroxyphenyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(cycloheptylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[([1,1′-biphenyl]-2-ylmethyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2-fluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(dimethylamino)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-naphthamide,N¹-[(1S,2R)-1-benzyl-3-({2-[({5-[(dimethylamino)methyl]-2-furyl}methyl)sulfanyl]ethyl}amino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-({2-[(2-chloro-6-fluorobenzyl)sulfanyl]ethyl}amino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[([1,1′-biphenyl]-4-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(1-naphthylamino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1H-imidazol-5-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-phenyl-1H-imidazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-imidazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(2-butyl-4-chloro-1H-imidazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-benzimidazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-hydroxy-1-naphthyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-oxo-4H-chromen-3-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-({[5-cyano-6-(methylsulfanyl)-2-pyridinyl]methyl}amino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,[5-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)-2-furyl]methylacetate,N¹-[(1S,2R)-3-[(1-benzofuran-3-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,methyl4-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)-1-methyl-1H-pyrrole-2-carboxylate,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({[1-(phenylsulfonyl)-1H-pyrrol-2-yl]methyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-pyrrol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-phenyl-1H-pyrazol-4-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(5-chloro-2-thienyl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-phenoxy-2-thienyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-quinolinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-quinolinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-indol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1-benzyl-1H-indol-3-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(l-methyl-1H-indol-3-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[({1-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl}methyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(2-butyl-1H-imidazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,methyl3-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)-1H-indole-6-carboxylate,3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-amino)carbonyl]-5-[butyl(butyryl)amino]benzyldiethyl phosphate,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(cyanomethyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(hydroxymethyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³,N³-dipropyl-5-prop-1-ynylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-fluorobenzyl)amino]-2-hydroxypropyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(8-quinolinyl)isophthalamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl})-4′-methoxy-N⁵,N⁵-dipropyl[l,1′-biphenyl]-3,5-dicarboxamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropyl[l,1′-biphenyl]-3,5-dicarboxamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropyl[1,1′-biphenyl]-3,5-dicarboxamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4′-[(dimethylamino)sulfonyl]-N⁵,N⁵-dipropyl-l,1′-biphenyl-3,5-dicarboxamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4′-[(dimethylamino)sulfonyl]-N⁵,N⁵-dipropyl-1,1′-biphenyl-3,5-dicarboxamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(3-thienyl)isophthalamide,N-{(1R,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-pentanoylbenzamide,N¹-(4-hydroxybutyl)-N³-{(1S)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N¹-propylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³-(3-hydroxypropyl)-5-methyl-N³-propylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3-(2,4-dimethylphenyl)propyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(4-methylphenyl)propyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1,3-dioxo-2-propyl-5-isoindolinecarboxamide,N-{(1R,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-bromo-5-methylbenzamide,3-bromo-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methylbenzamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N¹,N¹-dipropylisophthalamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(2-furyl)-5-methylbenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3′,5,5′-trimethyl-1,1′-biphenyl-3-carboxamide,3′-Acetyl-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl[1,1′-biphenyl]-3-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3′-methoxy-5-methyl[1,1′-biphenyl]-3-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl[1,1′-biphenyl]-3-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(2-thienyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(3-thienyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-methyl-5-(3-thienyl)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-3-(3-thienyl)benzamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³,N⁵,N⁵-tetrapropylbenzene-1,3,5-tricarboxamide,N¹-{(1S,2R)-1-(3,5-Difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylbenzene-1,3,5-tricarboxamide,Ethyl3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-[(dipropylamino)carbonyl]benzoate,N¹-{(1S,2R)-2-Hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropylbenzene-1,3,5-tricarboxamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,5-Amino-N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(trifluoroacetyl)amino]isophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(thien-2-ylsulfonyl)amino]isophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(thien-2-ylcarbonyl)amino]isophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(methacryloylamino)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(2,2-dimethylpropanoyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(phenylsulfonyl)amino]-N³,N³-dipropylisophthalamide.N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(methylthio)pentanamide,tert-butyl(2R,3S)-3-({3-[(dipropylamino)sulfonyl]-propanoyl}amino)-2-hydroxy-4-phenylbutyl(3-methoxybenzyl)carbamateN-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-[propionyl(propyl)amino]benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-butyl-1H-indole-5-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-bromo-5-methylbenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[butyl(propionyl)amino]-5-methylbenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-1-propyl-1H-indole-6-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-(1-propylbutyl)-1H-indole-6-carboxamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-[(dipropylamino)carbonyl]benzoicacid,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-prop-1-ynylisophthalamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-(dipropylamino)isonicotinamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-hydroxy-2-(4-methylphenyl)acetamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-hydroxy-N3-methylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-hydroxy-2-(4-methoxy-3-nitrophenyl)acetamide,5-(aminosulfonyl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-methoxybenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-hydroxy-3-(pyrrolidin-1-ylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(3,5-dimethylisoxazol-4-yl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1,3-thiazol-2-yl)isophthalamide,3-(cyclohexylcarbonyl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methylbenzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³-propylisophthalamide,3-[cyclohexyl(hydroxy)methyl]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methylbenzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(4-methyl-1,3-oxazol-2-yl)-N³,N³-dipropylisophthalamideN³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N⁵,N⁵-dipropylpyridine-3,5-dicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-1,2,4-oxadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-N⁵,N⁵-dipropylpyridine-3,5-dicarboxamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-N⁵,N⁵-dipropylpyridine-3,5-dicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(4-hydroxybut-1-ynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,1-{3-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]-5-methylbenzoyl}-L-prolinamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isopropyl-5-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-N³,5-dimethylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,5-dimethyl-N³-prop-2-ynylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isobutyl-5-methylisophthalamide,N¹-(sec-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-diethyl-5-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,5-dimethyl-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isopropyl-N³,5-dimethylisophthalamide,N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N¹,5-dimethylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isobutyl-N³,5-dimethylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-5-methyl-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-N³-isopropyl-5-methylisophthalamide,N¹,N¹-diallyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,3-(azepan-1-ylcarbonyl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylbenzamideN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(4-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(3-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylben)amino]-2-hydroxypropyl}-N³,N³-diisopropyl-5-methylisophthalamide,N-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N¹-ethyl-5-methylisophthalamide,N¹-(cyclopropylmethyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N¹-propylisophthalamide,1-{3-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]-5-methylbenzoyl}-D-prolinamide,N¹-cyclohexyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N¹,5-dimethylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-methylphenyl)cyclopropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N³-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(1,2,3,4-tetrahydronaphthalen-1-ylamino)propyl]-N⁵,N⁵-diisopropylpyridine-3,5-dicarboxamide,andN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(trifluoromethyl)sulfonyl]amino}benzamide.22. A substituted amine of formula (X) according to claim 21 which isselected from the group consisting of:N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-furlymethyl)amino-]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(2-hydroxyethoxy)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-3-[(2-aminobenzyl)amino]-1-benzyl-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(trifluoromethoxy)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,5-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethoxy)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[([1,1′-biphenyl]-3-ylmethyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,4-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-benzyl-2-hydroxy-3-[(3-methoxypropyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,4-dimethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino)-1-methyl-2-oxoethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(isobutylamino)-1-methyl-2-oxoethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(isobutylamino)-1-methyl-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N³-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(isobutylamino)-1-methyl-2-oxoethyl]amino}propyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino)-1,1-dimethyl-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino)-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(isobutylamino)carbonyl]propyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1R)-1-[(isobutylamino)carbonyl]propyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(isobutylamino)-2-methyl-3-oxopropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1S)-1-benzyl-2-(isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-1-[(isobutylamino)carbonyl]-2-methylpropyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-pyridinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1S)-1-[(benzyloxy)methyl]-2-(isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(isobutylamino)carbonyl]butyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-1-(hydroxymethyl)-2-(isobutylamino)-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenylethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isopentylamino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(cyclohexylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(butylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxypropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,(1R,3S)-5-{[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}-1,3-cyclohexanedicarboxylicacid,N¹-[(1S,2R)-3-[([1,1′-biphenyl]-3-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenylpropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1,3-thiazol-5-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-thienylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-pyrazinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethoxy)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-fluorobenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methoxy-N³,N³-dipropylisophthalamideN¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-chloro-N³,N³-dipropylisophthalamide,N³-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-fluoro-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-N3,N3-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1,3-thiazol-5-ylmethyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}[1,1′-biphenyl]-3-carboxamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³-(2-methoxyethyl)-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1R)-1,2,3,4-tetrahydro-1-naphthalenylamino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1R)-3-{[3,5-bis(trifluoromethyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-fluoro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3-fluoro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[4-fluoro-3-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[4-chloro-3-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-benzyl-2-hydroxy-3-[(3-nitrobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3-(difluoromethoxy)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-ethoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-bromo-4-fluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,5-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethoxybenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-methyl-1,3-thiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³-methyl-N³-propylisophthalamide,N³-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,isomer B,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-furylmethyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(tetrahydro-3-furanylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-propoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-pyridinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-hydroxy-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-methyl-1-(3-methylphenyl)ethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylamino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2,5-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[2-chloro-5-(trifluoromethyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-hydroxy-5-methylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,5-chloro-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1R)-1-(3-bromophenyl)ethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N¹,N¹-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-hydroxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-cyano-N³,N³-dipropylisophthalamidehydrochloride,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,5-(aminosulfonyl)-N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1-pyrrolidinylsulfonyl)isophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylamino)sulfonyl]-N³,N³-dipropylisophthalamide,N-{((1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(dimethylamino)sulfonyl]-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(dipropylamino)sulfonyl]propanamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-oxo-5-(1-piperidinyl)pentanamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-[(dipropylamino)sulfonyl]propanamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-ethyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-tert-butyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-cyano-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-propyl-1H-indole-6-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,4-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-aminobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N³-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}amino)propyl]-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,5-chloro-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N³,N³-bis(2-methoxyethyl)isophthalamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopentyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(dimethylamino)benzyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4,5-dimethyl-2-furyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopentyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopropyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2S)-tetrahydro-2-furanylmethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropenylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-propoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(hexylamino)-2-hydroxypropyl-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzamide,methyl4-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)benzoate,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-isoxazolylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,(1R,2R)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl)}-N²,N²-dipropyl-1,2-cyclopropanedicarboxamide,N³-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2S)-tetrahydro-2-furanylmethyl]amino}propyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N³-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide1-oxide, N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-oxabicyclo[2.2.1]hept-2-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-methyl-1,3-thiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-1,3-thiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(butylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(5-hexynylamino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N³-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-methyl-2-furyl)methyl]amino}propyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(2-furyl)-1-methylethyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-5-isoxazolyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isobutyl-1,3-thiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(dipropylamino)sulfonyl]propanamide,N¹-[(1S,2R)-3-[([1,1′-biphenyl]-4-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1H-imidazol-5-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-phenyl-1H-imidazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(2-butyl-4-chloro-1H-imidazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-({[5-cyano-6-(methylsulfanyl)-2-pyridinyl]methyl}amino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,[5-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)-2-furyl]methylacetate,N¹-[(1S,2R)-3-[(1-benzofuran-3-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,methyl4-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)-1-methyl-1H-pyrrole-2-carboxylate,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-pyrrol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(5-chloro-2-thienyl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-indol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1-benzyl-1H-indol-3-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-indol-3-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(2-butyl-1H-imidazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,methyl3-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)-1H-indole-6-carboxylate,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(cyanomethyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(hydroxymethyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³,N³-dipropyl-5-prop-1-ynylisophthalamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4′-methoxy-N⁵,N⁵-dipropyl[1,1′-biphenyl]-3,5-dicarboxamidehydrochloride,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropyl[1,1′-biphenyl]-3,5-dicarboxamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropy[1,1′-biphenyl]-3,5-dicarboxamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4′-[(dimethylamino)sulfonyl]-N⁵,N⁵-dipropyl-1,1′-biphenyl-3,5-dicarboxamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4′-[(dimethylamino)sulfonyl]-N⁵,N⁵-dipropyl-1,1′-biphenyl-3,5-dicarboxamide,N-{(1R,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-pentanoylbenzamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³-(3-hydroxypropyl)-5-methyl-N³-propylisophthalamide,N-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³,N⁵,N⁵-tetrapropylbenzene-1,3,5-tricarboxamide,N¹-{(1S,2R)-1-(3,5-Difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylbenzene-1,3,5-tricarboxamide,ethyl3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-[(dipropylamino)carbonyl]benzoate,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,5-amino-N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(thien-2-ylsulfonyl)amino]isophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(thien-2-ylcarbonyl)amino]isophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(methacryloylamino)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(phenylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(methylthio)pentanamide,3-amino-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-methylbutanamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-ethylhexanamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-[(isobutylsulfonyl)amino]propanamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³-(isobutylsulfonyl)-beta-alaninamide,5-bromo-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,andN¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-[(dipropylamino)carbonyl]benzoicacid,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-prop-1-ynylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-hydroxy-3-(pyrrolidin-1-ylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1,3-thiazol-2-yl)isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³-propylisophthalamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N⁵,N⁵-dipropylpyridine-3,5-dicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-1,2,4-oxadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-N⁵,N⁵-dipropylpyridine-3,5-dicarboxamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-N⁵,N⁵-dipropylpyridine-3,5-dicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(4-hydroxybut-1-ynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,1-{3-[({(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}amino)carbonyl]-5-methylbenzoyl}-L-prolinamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzy)amino]-2-hydroxypropyl}-N³-isopropyl-5-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-N³,5-dimethylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,5-dimethyl-N³-prop-2-ynylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isobutyl-5-methylisophthalamide,N¹-(sec-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-diethyl-5-methylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,5-dimethyl-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isopropyl-N³,5-dimethylisophthalamide,N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N¹,5-dimethylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isobutyl-N³,5-dimethylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-5-methyl-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-N³-isopropyl-5-methylisophthalamide,N¹,N¹-diallyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,3-(azepan-1-ylcarbonyl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylbenzamideN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(4-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(3-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-diisopropyl-5-methylisophthalamide,N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N¹-ethyl-5-methylisophthalamide,N¹-(cyclopropylmethyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N¹-propylisophthalamide,N¹-cyclohexyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N¹,5-dimethylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-methylphenyl)cyclopropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,andN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(trifluoromethyl)sulfonyl]amino}benzamide.23. A substituted amine of formula (X) according to claim 1 which isselected from the group consisting of:N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(2-propylpentanoyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(2-ethylpentanoyl)-5-methylbenzamide,N-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-methyl-5-(2-propylpentanoyl)benzamide,N-{(1S,2R)-1-benzyl-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-3-methyl-5-(2-propylpentanoyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(2-ethylbutanoyl)-5-methylbenzamide,N¹-{(1S,2R)-1-benzyl-3-(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(2-propylpentanoyl)isophthalaide,N-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(2-ethylpentanoyl)-5-methylbenzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(2-propylpentanoyl)isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hiydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(2-propylpentanoyl)isophthalamide,N-[(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propyl]-3-methyl-5-(2-propylpentanoyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(2-propylpentanoyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-methyl-5-(2-propylpentanoyl)benzamide,N¹-(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(3-pyridinyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(4-pyridinyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1-propynyl)isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-(1-propynyl)isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-(2-propynyl)isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(2-propynyl)isophthalamide,N¹-{(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(3-thienylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-[(1R)-2-(benzylamino)-1-hydroxyethyl]-3-butynyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(2-thienylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-3-(benzylamino)-1-[4-(benzyloxy)benzyl]-2-hydroxypropyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(cyclohexylmethyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(1-naphthylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,2,3,5-trideoxy-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-methoxybenzyl)amino]-1-S-phenyl-1-thio-D-erythro-pentitol,N¹-[(1S,2R)-3-(benzylamino)-1-(3-furylmethyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-methylbutyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(4-fluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(2-furylmethyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-[(1R)-2-(benzylamino)-1-hydroxyethyl]-3-methylbutyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹N¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(4-hydroxybenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-butynyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-butynyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,5-(benzylamino)-2,3,5-trideoxy-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-S-phenyl-1-thio-D-erythro-pentitol,N¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(4-hydroxybenzyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S)-1-[(1R)-2-(benzylamino)-1-hydroxyethyl]-3-methylbutyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3-furylmethyl)-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-methylbutyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-(benzylamino)-1-(4-fluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(2-furylmethyl)-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(1-naphthylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(2-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-3-(benzylamino)-1-[4-(benzyloxy)benzyl]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(3-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S)-1-[(1R)-2-(benzylamino)-1-hydroxyethyl]-3-butynyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-methylbutyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-[3-(hydroxymethyl)benzyl]-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-[3-(hydroxymethyl)benzyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-[3-(hydroxymethyl)benzyl]-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-[4-(hydroxymethyl)benzyl]-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-[4-(hydroxymethyl)benzyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-[4-(hydroxymethyl)benzyl]-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-ethylbenzyl)amino]-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-[3-(benzyloxy)-5-fluorobenzyl]-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-[3-(benzyloxy)-5-fluorobenzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(dipropylamino)sulfonyl]propanamide,N¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide,3-[(dipropylamino)sulfonyl]-N-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]propanamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]-N⁵,N⁵-dipropylpentanediamide,3-[(dipropylamino)sulfonyl]-N-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}propanamide,N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide,3-[(dipropylamino)sulfonyl]-N-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}propanamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide,3-[(dipropylamino)sulfonyl]-N-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}propanamide,N¹-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide,3-[(dipropylamino)sulfonyl]-N-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}propanamide,N¹-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropylpentanediamide,3-[(dipropylamino)sulfonyl]-N-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]propanamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]-N⁵,N⁵-dipropylpentanediamide,3-[(dipropylamino)sulfonyl]-N-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]propanamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]-N⁵,N⁵-dipropylpentanediamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-{[(2R)-1-ethylpyrrolidinyl]carbonyl}-5-methylbenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-{[(2S)-1-ethylpyrrolidinyl]carbonyl}-5-methylbenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(1-ethyl-1H-imidazol-2-yl)carbonyl]-5-methylbenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(1-ethyl-4-methyl-1H-imidazol-5-yl)carbonyl]-5-methylbenzamide,N¹-((1S,²S)-1-(3,5-difluorobenzyl)-2-hydroxy-2-{1-[(3-methoxybenzyl)amino]cyclopropyl}ethyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2S)-1-(3,5-difluorobenzyl)-2-{1-[(3-ethylbenzyl)amino]cyclopropyl}-2-hydroxyethyl)-5-methyl-N³,N³-dipropylisophthalamide,(1R,2R,3R)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N²,N²-dipropyl-1,2,3-cyclopropanetricarboxamide,(1R,2R,3R)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-phenyl-N²,N²-dipropyl-1,2-cyclopropanedicarboxamide,(1R,2R,3R)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-N²,N²-dipropyl-1,2-cyclopropanedicarboxamide,(1R,2R,3S)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-N²,N²-dipropyl-1,2-cyclopropanedicarboxamide,(1R,2R,3S)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-phenyl-N²,N²-dipropyl-1,2-cyclopropanedicarboxamide,(1R,2R,3S)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N²,N²-dipropyl-1,2,3-cyclopropanetricarboxamide,(1R,2R,3S)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl)-N²,N²-dipropyl-1,2-cyclopropanedicarboxamide,(1R,2R,3R)-3-(2-amino-2-oxoethyl)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N²,N²-dipropyl-1,2-cyclopropanedicarboxamide,(1R,2R,3S)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[2-(dipropylamino)-2-oxoethyl]-3-methylcyclopropanecarboxamide,(1R,2R,3R)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[2-(dipropylamino)-2-oxoethyl]-3-methylcyclopropanecarboxamide,(1S,2R,3R)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[2-(dipropylamino)-2-oxoethyl]-3-phenylcyclopropanecarboxamide,(1S,2R,3S)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[2-(dipropylamino)-2-oxoethyl]-3-phenylcyclopropanecarboxamide,(1S,2R,3R)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[2-(dipropylamino)-2-oxoethyl]-1,2-cyclopropanedicarboxamide,(1S,2R,3S)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[2-(dipropylamino)-2-oxoethyl]-1,2-cyclopropanedicarboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5{[(trifluoromethyl)sulfonyl]amino}isophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-{methyl[(trifluoromethyl)sulfonyl]amino}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-{methyl[(trifluoromethyl)sulfonyl]amino}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-{propyl[(trifluoromethyl)sulfonyl]amino}isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(phenylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-3-[(dipropylamino)sulfonyl]propanamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-3-[(dipropylamino)sulfonyl]propanamide,N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(dimethylamino)benzyl]amino}-2-hydroxypropyl)-3-[(dipropylamino)sulfonyl]propanamide,N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-1,3-thiazol-5-yl)methyl]amino}-2-hydroxypropyl)-3-[(dipropylamino)sulfonyl]propanamide,N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isobutyl-1,3-thiazol-5-yl)methyl]amino}propyl)-3-[(dipropylamino)sulfonyl]propanamide,N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-5-isoxazolyl)methyl]amino}propyl)-3-[(dipropylamino)sulfonyl]propanamide,N-[(1S,²R)-3-[(3-cyclopropylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-3-[(dipropylamino)sulfonyl]propanamide,N¹-[(1S,²R)-3-[(3-cyclopropylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1,3-thiazol-2-yl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1,3-oxazol-2-yl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-acetylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-acetylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-[(3-acetylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-(aminosulfonyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-acetylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-(methylsulfonyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[3-(diethylamino)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(4-morpholinyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1-piperazinyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[3-(aminosulfonyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({3-[(dimethylamino)sulfonyl]benzyl}amino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzy)-2-hydroxy-3-{[3-(1-piperidiylsulfonyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(methylsulfonyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(isopropylsulfonyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[3-(aminocarbonyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({3-[(dimethylamino)carbonyl]benzyl}amino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-cyanobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,3-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)phenylcarbamate,3-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)phenyldimethylcarbamate,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1-propynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(3-methyl-1-butynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(2-propynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(5-isobutyl-1,3,4-oxadiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(5-ethyl-1,3,4-oxadiazol-2-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(5-ethyl-1,3,4-thiadiazol-2-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(5-isobutyl-1,3,4-thiadiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(3-ethyl-1,2,4-thiadiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(3-isobutyl-1,2,4-thiadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(3-isobutyl-1,2,4-oxadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-1,3-oxazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isobutyl-1,3-oxazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-isobutyl-1,3,4-oxadiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-isobutyl-1,3,4-thiadiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(5-ethyl-1,3,4-thiadiazol-2-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(5-ethyl-1,3,4-oxadiazol-2-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3-ethyl-1,2,4-thiadiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-1,2,4-thiadiazol-5-yl)methyl]amino}propyl)-5-mty-3N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-1,2,4-oxadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-2H-tetraazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isobutyl-2H-tetraazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-4-pyrimidinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isopropyl-4-pyrimidinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethynyl-4-pyrimidinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(6-isopropyl-4-pyrimidinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({[6-(dimethylamino)-4-pyrimidinyl]methyl}amino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({[2-(dimethylamino)-4-pyrimidinyl]methyl}amino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({[4-(dimethylamino)-2-pyrimidinyl]methyl}amino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-isopropyl-2-pyrimidinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4-ethyl-2-pyrimidinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-[(5-ethyl-3-pyridazinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N³-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(dimethylamino)benzyl]amino}-2-hydroxypropyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-isopropyl-3-pyridazinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N³-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1-propynyl)benzyl]amino}propyl)-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(6-isopropyl-4-pyridazinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(6-ethyl-4-pyridazinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(6-ethyl-2-pyrazinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N⁵,N⁵-dipropyl-3,5-pyridinedicarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(6-isopropyl-2-pyrazinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3,4,5-trifluorobenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-2-hydroxy-1-(3,4,5-trifluorobenzyl)-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-2-hydroxy-1-(2,3,5,6-tetrafluorobenzyl)-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2,3,5,6-tetrafluorobenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1R,2S)-6-ethyl-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1R,2S)-6-ethyl-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-2-hydroxypropyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(1H-indol-5-ylmethyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-(1H-indol-5-ylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-methylbenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-methylbenzyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[3-(trifluoromethyl)benzyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[3-(trifluoromethyl)benzyl]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-pyridinylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-pyridinylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-[3-fluoro-5-(trifluoromethyl)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-[3-fluoro-5-(trifluoromethyl)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[3-(trifluoromethoxy)benzyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[3-(trifluoromethoxy)benzyl]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(3-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(3-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(4-methylbenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(4-methylbenzyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(4-fluoro-3-methylbenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(4-fluoro-3-methylbenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(4-chlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(4-chlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(3-methoxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(3-methoxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(4-methoxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(4-methoxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3-chloro-5-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-chloro-5-fluorobenzy)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(4-chloro-3-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(4-chloro-3-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3,5-dichlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-dichlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-[4-(dimethylamino)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-[4-(dimethylamino)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3-chlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-chlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(4-isopropylbenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(4-isopropylbenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzy)amino]-1-[(6-methoxy-2-pyridinyl)methyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[(6-methoxy-2-pyridinyl)methyl]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[(5-methyl-2-pyridinyl)methyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[(5-methyl-2-pyridinyl)methyl]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3-fluoro-4-methylbenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-fluoro-4-methylbenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3-fluoro-4-methoxybenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-fluoro-4-methoxybenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-methoxy-5-methylbenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-methoxy-5-methylbenzyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1,3-thiazol-2-ylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1,3-thiazol-2-ylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-[(5-chloro-2-thienyl)methyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-[(5-chloro-2-thienyl)methyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(1-pyrrolidinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(propylsulfonyl)amino]-1,3-thiazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-3-(1-pyrrolidinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[(propylsulfonyl)amino]-1,3-thiazole-4-carboxamide,N-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl]amino}-2-hydroxypropyl)-4-hydroxy-3-(1-pyrrolidinylcarbonyl)benzamide,N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl]amino}-2-hydroxypropyl)-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl]amino}-2-hydroxypropyl)-5-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-4-hydroxy-3-(1-pyrrolidinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-5-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-3-(1-piperidinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-4-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl)}-4-hydroxy-3-(1-piperidinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-4-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(4-morpholinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-[(ethylsulfonyl)amino]-1,3-oxazole-2-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}⁴-[(ethylsulfonyl)amino]-1,3-oxazole-2-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(4-morpholinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-[(propylsulfonyl)amino]-1,3-oxazole-2-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-[(methylsulfonyl)amino]-I,3-thiazole-2-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-3-(1-piperazinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-[(methylsulfonyl)amino]-1,3-thiazole-2-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-5-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(1-piperazinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-5-carboxamide,N⁴-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4,5-dicarboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-5-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-methylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-methyl-2-[(methylsulfonyl)amino]-1,3-oxazole-5-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(ethylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-N³-methylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-methyl-5-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[(ethylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-methyl-5-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³-ethyl-4-hydroxyisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(methylsulfonyl)amino]-1,3-oxazole-2-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(ethylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(methylsulfonyl)amino]-3-isoxazolecarboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-4-hydroxyisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-[(methylsulfonyl)amino]-3-isoxazolecarboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(propylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-[(methylsulfonyl)amino]-5-isoxazolecarboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³-ethyl-4-hydroxyisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(methylsulfonyl)amino]-5-isoxazolecarboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[(propylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-(hydroxymethyl)-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N³-(cyclopropylmethyl)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-hydroxyisophthalamide,5-cyclopropyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(propylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-isopropyl-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N³-(cyclopropylmethyl)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxyisophthalamide,N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isopentylamino)propyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-2-[(propylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-[(1S,2R)-3-(cyclopropylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N-[(1S,²R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-isobutylisophthalamide,2-{[(cyclopropylmethyl)sulfonyl]amino}-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1,3-oxazole-4-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-isobutyl-N³-methylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(isobutylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N³-(cyclopropylmethyl)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-methylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-[(isobutylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-methyl-N³-propylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(isobutylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-N³-methyl-N³-propylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(phenylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³-ethyl-4-hydroxy-N³-propylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-{[(4-methylphenyl)sulfonyl]amino}-1,3-oxazole-4-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-4-hydroxy-N³-propylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-{[(4-methylphenyl)sulfonyl]amino}-1,3-oxazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(phenylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-hydroxy-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl})-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(ethylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-[(propylsulfonyl)amino]isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(isopropylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(isobutylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-[(thien-2-ylsulfonyl)amino]isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(2-furylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-[(1,3-thiazol-5-ylsulfonyl)amino]isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(1,3-oxazol-5-ylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(1,3-oxazol-4-ylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-[(1,3-thiazol-4-ylsulfonyl)amino]isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}-N³N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(phenylsulfonyl)amino]-N³,N³-dipropylisophthalamide,5-{[(5-cyanopyridin-2-yl)sulfonyl]amino}-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-({[5-(trifluoromethyl)pyridin-2-yl]sulfonyl}amino)isophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-({[5-(trifluoromethyl)pyridin-2-yl]sulfonyl}amino)benzamide,3-{[(5-cyanopyridin-2-yl)sulfonyl]amino}-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(phenylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(methylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(ethylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(propylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(isobutylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(isopropylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(1-ethylpropyl)sulfonyl]amino}benzamide,3-[(cyclohexylsulfonyl)amino]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(1-propylbutyl)sulfonyl]amino}benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(thien-2-ylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(2-furylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(isoxazol-5-ylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(isoxazol-3-ylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(3-furylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(thien-3-ylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1,3-thiazol-4-ylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1,3-thiazol-5-ylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1,3-thiazol-2-ylsulfonyl)amino]benzamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isopentylamino)propyl]-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,N¹-[(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,N¹-[(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isopentylamino)propyl]-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-(tert-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isophthalamide,N¹-(tert-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,5-bromo-N¹-(tert-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isophthalamide,3-tert-butoxy-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}benzamide,3-tert-butoxy-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylbenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(trifluoromethyl)sulfonyl]amino}benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(trifluoromethoxy)benzamide,andN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-methyl-5-(trifluoromethoxy)benzamide.24. A method of treating a patient who has, or in preventing a patientfrom getting, a disease or condition selected from the group consistingof Alzheimer's disease, for helping prevent or delay the onset ofAlzheimer's disease, for treating patients with mild cognitiveimpairment (MCI) and preventing or delaying the onset of Alzheimer'sdisease in those who would progress from MCI to AD, for treating Down'ssyndrome, for treating humans who have Hereditary Cerebral Hemorrhagewith Amyloidosis of the Dutch-Type, for treating cerebral amyloidangiopathy and preventing its potential consequences, i.e. single andrecurrent lobar hemorrhages, for treating other degenerative dementias,including dementias of mixed vascular and degenerative origin, dementiaassociated with Parkinson's disease, dementia associated withprogressive supranuclear palsy, dementia associated with cortical basaldegeneration, diffuse Lewy body type of Alzheimer's disease and who isin need of such treatment which comprises administration of atherapeutically effective amount of a compound selected from the groupconsisting of a substituted amine of formula (X)

where R₁ is: —(CH₂)_(n-1)—(R_(1-aryl)) where n₁ is one and whereR_(1-aryl) is phenyl optionally substituted with one, two, three, orfour of the following substituents on the aryl ring: (A) C₁–C₆ alkyloptionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, —C≡N,—CF₃, C₁–C₃ alkoxy, (B) C₂–C₆ alkenyl with one or two double bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, (C)C₂–C₆ alkynyl with one or two triple bonds, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, (D) —F, Cl, —Br or —I, (F)—C₁–C₆ alkoxy optionally substituted with one, two, or three of: —F, (G)—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are as defined below, (H)—OH, (I) —C≡N, (J) C₃–C₇ cycloalkyl, optionally substituted with one,two or three substituents selected from the group consisting of —F, —Cl,—OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a)and R_(1-b) are —H or C₁–C₆ alkyl, (K) —CO—(C₁–C₄ alkyl), (L)—SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (M)—CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, or(N) —SO₂—(C₁–C₄ alkyl), where R₂ is: (I) —H, (II) C₁–C₆ alkyl,optionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areas define above, (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) orR_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as definedabove; (IV) C₂–C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, (V) C₂–C₆ alkynyl with one ortwo triple bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are —H or C₁–C₆ alkyl, or (VI) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl; whereR₃ is: (I) —H, (II) C₁–C₆ alkyl, optionally substituted with one, two orthree substituents selected from the group consisting of C₁–C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as define above, (III)—(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or R_(1-heteroaryl) whereR_(1-aryl) and R_(1-heteroaryl) are as defined above; (IV) C₂–C₆ alkenylwith one or two double bonds, (V) C₂–C₆ alkynyl with one or two triplebonds, or (VI) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,  and where R₂ and R₃ aretaken together with the carbon to which they are attached to form acarbocycle of three, four, five, six or seven carbon atoms, optionallywhere one carbon atom is replaced by a heteroatom selected from thegroup consisting of —O—, —S—, —SO₂—, and —NR_(N-2)—, where R_(N-2) is asdefined below; where R_(N) is: (I) R_(N-1)—X_(N)— where X_(N) is —CO—;where R_(N-1) is R_(N-aryl) where R_(N-aryl) is phenyl optionallysubstituted with one, two or three of the following substituents whichcan be the same or different and are: (1) C₁–C₆ alkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (2) —OH, (3) NO₂, (4) —F, —Cl, —Br, or —I, (5) —CO—OH, (6) —C≡N,(7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the sameor different and are selected from the group consisting of: (a) —H, (b)—C₁–C₆ alkyl optionally substituted with one substituent selected fromthe group consisting of: (i) —OH, and (ii) —NH₂, (c) —C₁–C₆ alkyloptionally substituted with one to three —F, —Cl, —Br, or —I, (d) —C₃–C₇cycloalkyl, (e) —(C₁–C₂ alkyl)(C₃–C₇ cycloalkyl), (f) —(C₁–C₆alkyl)—O—(C₁–C₃ alkyl), (g) —C₂–C₆ alkenyl with one or two double bonds,(h) —C₂–C₆ alkynyl with one or two triple bonds, (i) —C₁–C₆ alkyl chainwith one double bond and one triple bond, (j) R_(1-aryl) whereR_(1-aryl) is as defined above, and (k) R_(1-heteroaryl) whereR_(1-heteroaryl) is as defined above, (8) —(CH₂)₀₋₄—CO—(C₁–C₁₂ alkyl),(9) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkenyl with one, two or three double bonds),(10) —(CH₂)₀₋₄—CO—(C₂-C₁₂ alkynyl with one, two or three triple bonds),(11) —(CH₂)₀₋₄—CO—(C₃–C₇ cycloalkyl), (12) (CH₂)₀₋₄—CO—R_(1-aryl) whereR_(1-aryl) is as defined above, (13) —(CH₂)₀₋₄—CO—R_(1-heteroaryl) whereR_(1-heteroaryl) is as defined above, (14)—(CH₂)₀₋₄—CO—R_(1-heterocycle) where R_(1-heterocycle) is as definedabove, (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected from thegroup consisting of morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S, S-dioxide, pyrrolinyl and pyrrolidinylwhere each group is optionally substituted with one, two, three, or fourof: C₁–C₆ alkyl, (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selectedfrom the group consisting of: (a) C₁–C₆ alkyl, (b)—(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above, (c) C₂–C₆alkenyl containing one or two double bonds, (d) C₂–C₆ alkynyl containingone or two triple bonds, (e) C₃–C₇ cycloalkyl, and (f)(CR2)₀₋₂—(R_(1-heteroaryl)) where R_(1-heteroaryl) is as defined above,(17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are asdefined above, (18) —(CH₂)₀₋₄—SO—(C₁–C₈ alkyl), (19)—(CH₂)₀₋₄—SO₂—(C₁–C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂—(C₃–C₇ cycloalkyl),(21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can be thesame or different and is as defined above, (22) —(CH₂)₀₋₄—N(H orR_(N-5))—CO—N(R_(N-5))₂, where R_(N-5) can be the same or different andis as defined above, (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) canbe the same or different and is as defined above, (24) —(CH₂)₀₋₄—N(—H orR_(N-5))—CO—R_(N-2) where R_(N-5) and R_(N-2) can be the same ordifferent and are as defined above, (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) whereR_(N-2) and R_(N-3) can be the same or different and are as definedabove, (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above, (27)—(CH₂)₀₋₄—O—CO—(C₁–C₆ alkyl), (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂where R_(N-aryl-1) is —H or C₁–C₄ alkyl, (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂where R_(N-5) is as defined above, (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂ whereR_(N-5) is as defined above, (31) —(CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5)is as defined above, (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) isas defined above, (33) —(CH₂)₀₋₄—S—(R_(N-5))₂ where R_(N-5) is asdefined above, (34) —(CH₂)₀₋₄—O—(C₁–C₆ alkyl optionally substituted withone, two, three, four, or five —F), (35) C₃–C₇ cycloalkyl, (36) C₂–C₆alkenyl with one or two double bonds optionally substituted with C₁–C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (37)C₂–C₆ alkynyl with one or two triple bonds optionally substituted withC₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (38)—(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5) and R_(N-2) can bethe same or different and are as described above, or (39)—(CH₂)₀₋₄—C₃–C₇ cycloalkyl, where R_(C) is: (I) —C₁–C₁₀ alkyl optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆alkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, —OC═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, —S(═O)₀₋₂ R_(1-a) where R_(1-a) is as defined above,—NR_(1-a)C═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, —C═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, and —S(═O)₂NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (II) —(CH₂)₀₋₃—(C₃–C₈) cycloalkyl where cycloalkyl can beoptionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁–C₆ alkoxy, —O-phenyl, —CO—OH, —CO—O—(C₁–C₄ alkyl), and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (III)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) where R_(C-x) and R_(C-y) are —H, C₁–C₄alkyl optionally substituted with one or two —OH, C₁–C₄ alkoxyoptionally substituted with one, two, or three of: —F, (CH₂)₀₋₄—C₃–C₇cycloalkyl, C₂–C₆ alkenyl containing one or two double bonds, C₂–C₆alkynyl containing one or two triple bonds, phenyl-, and where R_(C-x)and R_(C-y) are taken together with the carbon to which they areattached to form a carbocycle of three, four, five, six, or seven carbonatoms, optionally where one carbon atom is replaced by a heteroatomselected from the group consisting of —O—, —S—, —SO₂—, and —NR_(N-2)—and R_(C-aryl) is the same as R_(N-aryl); (IV)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl) where R_(C-heteroaryl) is thesame as R_(N-heteroaryl) and R_(C-x) and R_(C-y) are as defined above,(V) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-aryl) where R_(C-aryl),R_(C-x) and R_(C-y) are as defined above, (VI)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-heteroaryl) where R_(C-aryl),R_(C-heteroaryl), R_(C-x) and R_(C-y) are as defined above, (VII)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-aryl) whereR_(C-heteroaryl), R_(C-aryl), R_(C-x) and R_(C-y) are as defined above,(VIII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-heteroaryl) whereR_(C-heteroaryl), R_(C-x) and R_(C-y) are as defined above, (IX)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-heterocycle) where R_(C-aryl),R_(C-x) and R_(C-y) are as defined above, and R_(C-heterocycle) is thesame as R_(N-heterocycle), (X)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-heterocycle) whereR_(C-heteroaryl), R_(C-heterocycle), R_(C-x) and R_(C-y) are as definedabove, (XI) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-aryl) whereR_(C-heterocycle), R_(C-aryl), R_(C-x) and R_(C-y) are as defined above,(XII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-heteroaryl) whereR_(C-heterocycle), R_(C-heteroaryl), R_(C-x) and R_(C-y) are as definedabove, (XIII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-heterocycle)where R_(C-heterocycle), R_(C-x) and R_(C-y) are as defined above, (XIV)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle) where R_(C-heterocycle), R_(C-x)and R_(C-y) are as defined above, (XV)—[C(R_(C-1))(R_(C-2))]₁₋₃—CO—N(R_(C-3))₂ where R_(C-1) and R_(C-2) arethe same or different and are selected from the group consisting of: (A)—H, (B) —C₁–C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁–C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O— phenyl, andNR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (C)C₂–C₆ alkenyl with one or two double bonds, optionally substituted withone, two or three substituents selected from the group consisting ofC₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O—phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (D) C₂–C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areas defined above, (E) —(CH₂)₁₋₂—S(O)₀₋₂—(C₁–C₆ alkyl), (F)—(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of C₁–C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O— phenyl,—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (G)—(C₁–C₄ alkyl)—R_(C′-aryl) where R_(C′-aryl) is as defined forR_(1-aryl), (H) —(C₁–C₄ alkyl)—R_(C-heteroaryl) where R_(C-heteroaryl)is as defined above, (I) —(C₁–C₄ alkyl)—R_(C-heterocycle) whereR_(C-heterocycle) is as defined above, (J) —R_(C-heteroaryl) whereR_(C-heteroaryl) is as defined above, (K) —R_(C-heterocycle) whereR_(C-heterocycle) is as defined above, (M)—(CH₂)₁₋₄—R_(C-4)—(CH₂)₀₋₄—R_(C′-aryl) where R_(C-4) is —O—, —S— or—NR_(C-5)— where R_(C-5) is C₁–C₆ alkyl, and where R_(C′-aryl) is asdefined above, (N) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₀₋₄—R_(C-heteroaryl) whereR_(C-4) and R_(C-heteroaryl) are as defined above, and (O) R_(C′-aryl)where R_(C′-aryl) is as defined above, and where R_(C-3) is the same ordifferent and is: (A) —H, (B) —C₁–C₆ alkyl optionally substituted withone, two or three substituents selected from the group consisting ofC₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O—phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (C) C₂–C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areas defined above, (D) C₂–C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁–C₆ alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, (E) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areas defined above, (F) —R_(C′-aryl) where R_(C′-aryl) is as definedabove, (G) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above,(H) —R_(C-heterocycle) where R_(C-heterocycle) is as defined above, (I)—(C₁–C₄ alkyl)—R_(C′-aryl) where R_(C′-aryl) is as defined above, (J)—(C₁–C₄ alkyl)—R_(C-heteroaryl) where R_(C-heteroaryl) is as definedabove, or (K) —(C₁–C₄ alkyl)—R_(C-heterocycle) where R_(C-heterocycle)is as defined above, (XVI) —CH(R_(C-aryl))₂ where R_(C-aryl) are thesame or different and are as defined above, (XVII)—CH(R_(C-heteroaryl))₂ where R_(C-heteroaryl) are the same or differentand are as defined above, (XVIII) —CH(R_(C-aryl))(R_(C-heteroaryl))where R_(C-aryl) and R_(C-heteroaryl) are as defined above, (XIX)cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to R_(C-aryl) orR_(C-heteroaryl) or R_(C-heterocycle) where R_(C-aryl) orR_(C-heteroaryl) or R_(C-heterocycle) are as defined above where onecarbon of cyclopentyl, cyclohexyl, or -cycloheptyl is optionallyreplaced with NH, NR_(N-5), O, or S(═O)₀₋₂, and where cyclopentyl,cyclohexyl, or -cycloheptyl can be optionally substituted with one ortwo —C₁–C₃ alkyl, —F, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, ═O, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (XX)C₂–C₁₀ alkenyl containing one or two double bonds optionally substitutedwith one, two or three substituents selected from the group consistingof C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy,—O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (XXI) C₂–C₁₀ alkynyl containing one or two triple bondsoptionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁–C₆ alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, (XXI)—(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁—R_(C-aryl) where R_(C-aryl) is as definedabove and R_(C-6) is —(CH₂)₀₋₆—OH, (XXII)—(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁—R_(C-heteroaryl) where R_(C-heteroaryl) andR_(C-6) is as defined above, (XXIII) —CH(—R_(C-aryl) orR_(C-heteroaryl))—CO—O(C₁–C₄ alkyl) where R_(C-aryl) andR_(C-heteroaryl) are as defined above, (XXIV)—CH(—CH₂—OH)—CH(—OH)-phenyl-NO₂, (XXV) (C₁–C₆ alkyl)—O—(C₁–C₆ alkyl)—OH,(XXVII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂, (XXVIII) —H, or (XXIX)—(CH₂)₀₋₆—C(═NR_(1-a))(NR_(1-a)R_(1-b)) where R_(1-a) and R_(1-b) are asdefined above; or a pharmaceutically acceptable salt thereof.
 25. Amethod of treatment according to claim 24, wherein the disease isAlzheimer's disease.
 26. A method of treatment according to claim 24,wherein the method is helping prevent or delay the onset of Alzheimer'sdisease.
 27. A method of treatment according to claim 24, wherein thedisease is mild cognitive impairment.
 28. A method of treatmentaccording to claim 24, wherein the disease is Down's syndrome.
 29. Amethod of treatment according to claim 24, wherein the disease isHereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.
 30. Amethod of treatment according to claim 24, wherein the disease iscerebral amyloid angiopathy.
 31. A method of treatment according toclaim 24, wherein the disease is degenerative dementias.
 32. A method oftreatment according to claim 24, wherein the disease is diffuse Lewybody type of Alzheimer's disease.
 33. A method of treatment according toclaim 24, wherein the method is treating an existing disease.
 34. Amethod of treatment according to claim 24, wherein the method ispreventing a disease from developing.
 35. A method of treatmentaccording to claim 24, wherein the therapeutically effective amount fororal administration is from about 0.1 mg/day to about 1,000 mg/day; forparenteral, sublingual, intranasal, intrathecal administration is fromabout 0.5 to about 100 mg/day; for depo administration and implants isfrom about 0.5 mg/day to about 50 mg/day; for topical administration isfrom about 0.5 mg/day to about 200 mg/day; for rectal administration isfrom about 0.5 mg to about 500 mg.
 36. A method of treatment accordingto claim 35, wherein the therapeutically effective amount for oraladministration is from about 1 mg/day to about 100 mg/day and forparenteral administration is from about 5 to about 50 mg daily.
 37. Amethod of treatment according to claim 36 where the therapeuticallyeffective amount for oral administration is from about 5 mg/day to about50 mg/day.
 38. A method of treatment according to claim 24 where: whereR₁ is: —(CH₂)₀₋₁—(R_(1-aryl)) where R_(N) is: R_(N-1)—X_(N),— whereX_(N) is —CO—, where R_(N-1) is —R_(N-aryl), and where R_(C) is: —C₁–C₈alkyl, —(CH₂)₀₋₃—(C₃–C₇) cycloalkyl, —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl),—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl),—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle), or -cyclopentyl or -cyclohexylring fused to R_(C-aryl) or R_(C-heteroaryl) or R_(C-heterocycle).
 39. Amethod of treatment according to claim 38 where: where R₂ is —H; whereR₃ is —H; where R_(N) is: R_(N-1)—X_(N)— where X_(N) is: —CO—, whereR_(N-1) is —R_(N-aryl), where R_(C) is: —(CH₂)₀₋₃—(C₃–C₇) cycloalkyl,—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl),—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl),—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle), or -cyclopentyl or -cyclohexylring fused to a R_(C-aryl) or R_(C-heteroaryl) or R_(C-heterocycle). 40.A method of treatment according to claim 39 where R_(C) is:—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl),—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl), or -cyclopentyl or -cyclohexylring fused to a R_(C-aryl) or R_(C-heteroaryl) or R_(C-heterocycle). 41.A method of treatment according to claim 24 where R₁ is:—(CH₂)—(R_(1-aryl)) where R_(1-aryl) is phenyl.
 42. A method oftreatment according to claim 41 where R₁ is: —(CH₂)—(R_(1-aryl)) whereR_(1-aryl) is phenyl substituted with two —F.
 43. A method of treatmentaccording to claim 42 where the —F substitution is 3,5-difluorobenzyl.44. A method of treatment according to claim 24 where R₂ is —H.
 45. Amethod of treatment according to claim 24 where R₃ is —H.
 46. A methodof treatment according to claim 24 where R_(N) is R_(N-1)—X_(N)— whereX_(N) is —CO—, where R_(N-1) is R_(N-aryl) where R_(N-aryl) is phenylsubstituted with one —CO—NR_(N-2)R_(N-3) where the substitution onphenyl is 1,3-.
 47. A method of treatment according to claim 46 whereR_(N-2) and R_(N-3) are the same and are C₃ alkyl.
 48. A method oftreatment according to claim 24 where R_(N) is R_(N-1)—X_(N)— whereX_(N) is —CO—, where R_(N-1) is R_(N-aryl) where R_(N-aryl) is phenylsubstituted with one C₁ alkyl and with one —CO—NR_(N-2)R_(N-3) where thesubstitution on the phenyl is 1,3,5-.
 49. A method of treatmentaccording to claim 48 where R_(N-2) and R_(N-3) are the same and are C₃alkyl.
 50. A method of treatment according to claim 24 where R_(N) isR_(N-1)—X_(N)— where X_(N) is —CO—, where R_(N-1) is R_(N-heteroaryl)where R_(N-heteroaryl) is substituted with one —CO—NR_(N-2)R_(N-3). 51.A method of treatment according to claim 50 where R_(N-2) and R_(N-3)are the same and are —C₃ alkyl.
 52. A method of treatment according toclaim 24 where R_(C) is: —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) whereR_(C-aryl) is phenyl, —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl), or-cyclopentyl or -cyclohexyl ring fused to a R_(C-aryl) orR_(C-heteroaryl) or R_(C-heterocycle).
 53. A method of treatmentaccording to claim 52 where R_(C) is: —(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)where R_(C-aryl) is phenyl.
 54. A method of treatment according to claim53 where phenyl is substituted in the 3-position or 3,5-positions.
 55. Amethod of treatment according to claim 52 where R_(C) is:—(CH₂)—R_(C-heteroaryl).
 56. A method of treatment according to claim 52where R_(C) is: —(CH₂)—R_(C-heterocycle).
 57. A method of treatmentaccording to claim 52 where R_(C) is: -cyclohexyl ring fused to a phenylring.
 58. A method of treatment according to claim 24 where thepharmaceutically acceptable salt is selected from the group consistingof salts of the following acids acetic, aspartic, benzenesulfonic,benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate,camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic,esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic,glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic,hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic,lactobionic, maleic, malic, malonic, mandelic, methanesulfonic,methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic,p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogenphosphoric, dihydrogen phosphoric, phthalic, polygalactouronic,propionic, salicylic, stearic, succinic, succinic, sulfamic, sulfanilic,sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic.
 59. Amethod of treatment according to claim 24 where the substituted amine(X) is selected from the group consisting of:N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-furylmethyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(ethylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(benzylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(isopropylamino)propyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(4-toluidino)propyl]-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(4-methoxyphenyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,ethyl{[(3S)-3-({3-[(dipropylamino)carbonyl]benzoyl}amino)-2-hydroxy-4-phenylbutyl]amino}(phenyl)acetate,N¹-((1S)-1-benzyl-2-hydroxy-3-{[(1S)-2-hydroxy-1-(hydroxymethyl)-2-(4-nitrophenyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2-chlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(4-chlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(2-hydroxyethoxy)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(2,3-dihydro-1H-inden-1-ylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-hydroxypropyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(tetrahydro-2-furanylmethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,2-diethoxyethyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(butylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(cyclohexylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-pyridinylmethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-3-[(2-aminobenzyl)amino]-1-benzyl-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-pyridinylmethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(1-pyrrolidinyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-hydroxy-2-phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-butoxypropyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-isopropoxypropyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(isopentylamino)propyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-phenylpropyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-methoxyethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-phenoxyethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-propoxyethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,3-dimethylbutyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-phenylbutyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-benzyl-2-hydroxy-3-[(4-nitrobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-chlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(4-chlorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(2-pyridinyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-pyridinylmethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,3-dimethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(trifluoromethoxy)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2-chloro-6-phenoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[4-(trifluoromethyl)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,3-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,5-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,5-difluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[4-(trifluoromethoxy)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-1-benzyl-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-methylbenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3,4,5-trimethoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethoxy)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,4-dimethoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[([1,1′-biphenyl]-3-ylmethyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,4-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2-fluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-methylbenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-1-phenylethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-1-phenylethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3,5-bis(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(trifluoromethyl)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-1-(1-naphthyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-1-(1-naphthyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-hydroxy-3-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,4-dihydroxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-benzyl-2-hydroxy-3-[(3-methoxypropyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-2-hydroxy-1-methylethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-2-hydroxy-1-methylethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(2-propynylamino)propyl]-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(2-fluorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(3-fluorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(4-fluorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(4-bromophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S)-1-benzyl-2-hydroxy-3-{[2-(3-methoxyphenyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(2,4-dichlorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(3-chlorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S)-1-benzyl-3-{[2-(2,5-dimethoxyphenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(4-methylphenyl)ethyl]amino}propyl)-N¹,N¹-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[(1R)-1-benzyl-2-hydroxyethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(4-morpholinyl)propyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propyl]-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(4-morpholinyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-hydroxybutyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(2-thienyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(4-hydroxybutyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S)-2-hydroxy-1-phenylethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,4-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R)-2-hydroxy-1-phenylethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(4-tert-butylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(1-phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,4-dimethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino)-1-methyl-2-oxoethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(isobutylamino)-1-methyl-2-oxoethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino)-1,1-dimethyl-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino)-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(isobutylamino)carbonyl]propyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1R)-1-[(isobutylamino)carbonyl]propyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(ethylamino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isobutylamino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(isobutylamino)-2-methyl-3-oxopropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[4-(dimethylamino)benzyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1S)-1-benzyl-2-(isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(isobutylamino)carbonyl]-2-methylpropyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[2-(dimethylamino)ethyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-pyridinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1S)-1-[(benzyloxy)methyl]-2-(isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1R)-1-[(isobutylamino)carbonyl]-2-methylpropyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(isobutylamino)carbonyl]butyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-1-(hydroxymethyl)-2-(isobutylamino)-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenylethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1S)-2-(benzylamino)-1-methyl-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-1-phenylpropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-2-(ethylamino)-1-methyl-2-oxoethyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(isobutylamino)-2-oxo-1-phenylethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isopentylamino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(cyclohexylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(butylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxypropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-hydroxy-2-phenylethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3R,5S)-3,5-dimethoxycyclohexyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,dimethyl(1R,3S)-5-{[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]aminol}-1,3-cyclohexanedicarboxylate,(1R,3S)-5-{[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}-1,3-cyclohexanedicarboxylicacid,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R)-1-phenylpropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-chlorobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(2-propylpentyl)sulfonyl]benzamide,N¹-[(1S,2R)-3-[([1,1′-biphenyl]-3-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenylpropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1,3-thiazol-5-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-thienylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-pyrazinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,5-difluorobenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-3-[(1,3-benzodioxol-5-ylmethyl)amino]-1-benzyl-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethoxy)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-fluorobenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-methyl-2-furyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(1,2,3,4-tetrahydro-1-naphthalenylamino)propyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methoxy-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-chloro-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-fluoro-N³,N³-dipropylisophthalamide,N-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-3-(4-morpholinylcarbonyl)benzamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1R)-1-[(benzyloxy)methyl]-2-(isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R)-1-(hydroxymethyl)-2-(isobutylamino)-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(pentylamino)propyl]-N³,N³-dipropylisophthalamide,N¹-[(1S)-3-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-1-benzyl-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,3-benzoyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}[1,1′-biphenyl]-3-carboxamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³-(2-methoxyethyl)-N³-propylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-ethoxybenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-2-naphthamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1R)-1,2,3,4-tetrahydro-1-naphthalenylamino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1R)-3-{[3,5-bis(trifluoromethyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-fluoro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,3-difluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3-fluoro-4-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2,5-difluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3-fluoro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,4-difluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[4-fluoro-3-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-chloro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[4-chloro-3-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(2,3-dihydro-1H-inden-2-ylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-benzyl-2-hydroxy-3-[(3-nitrobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3-(difluoromethoxy)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-ethoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(5-methyl-2-pyrazinyl)methyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-bromo-4-fluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,5-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethoxybenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isobutoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-methyl-1,3-thiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³-methyl-N³-propylisophthalamide,N¹-[(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(1,2-diphenylethyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,isomer A,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,isomer B,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(dimethylamino)benzamide,N-[(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl]-2-methyl-1H-benzimidazole-5-carboxamide,3-(aminosulfonyl)-N-{(1S)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-chlorobenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-cyanobenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-chloro-3-nitrobenzamide,methyl3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-nitrobenzoate,tert-butyl3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]phenylcarbamate,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-fluoro-5-(trifluoromethyl)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(trifluoromethyl)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-(butylamino)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(trifluoromethoxy)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3,5-dimethoxybenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3,5-dimethylbenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3,5-difluorobenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3,5-dichlorobenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-(benzyloxy)benzamide,3-(acetylamino)-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}benzamide,4-(acetylamino)-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}benzamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3,5-dimethyl-4-isoxazolyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-phenylpropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-furylmethyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(tetrahydro-3-furanylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-propoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-pyridinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-hydroxy-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-methyl-1-(3-methylphenyl)ethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylamino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2,5-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[2-chloro-5-(trifluoromethyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-hydroxy-5-methylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,5-chloro-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(1-benzofuran-2-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1R)-1-(3-bromophenyl)ethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[butyl(butyryl)amino]-5-methylbenzamide,N¹-{1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide,N³-{1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N¹,N¹-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-anilino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,5-bromo-N¹-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-hydroxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-cyano-N³,N³-dipropylisophthalamidehydrochloride,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,5-(aminosulfonyl)-N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1-pyrrolidinylsulfonyl)isophthalamide,N^(l)-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylamino)sulfonyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(dimethylamino)sulfonyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-ethyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-isobutyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-tert-butyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-cyano-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dimethyl-N⁵,N⁵-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-amino-1-benzyl-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(isopentylamino)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³-propyl-1,3,5-benzenetricarboxamide,N-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[butyryl(propyl)amino]-5-methylbenzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,4-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-aminobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-methylbenzamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(1H-isoindol-3-ylamino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R,2S,5R)-2-isopropyl-5-methylcyclobexyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹,N¹-diallyl-5-chloro-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}isophthalamide,N¹,N¹-diallyl-5-chloro-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(dimethylamino)benzyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4,5-dimethyl-2-furyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopentyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(cyclopropylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(cyclopropylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(tetrahydro-2-furanylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-oxo-3-azepanyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-methyl-2-furyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2S)-tetrahydro-2-furanylmethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,5-chloro-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N³,N³-di(2-propynyl)isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropenylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-propoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(hexylamino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzamide,methyl4-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)benzoate,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-isoxazolylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,4-(butyrylamino)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}benzamide,N¹-[(1S,2R)-3-[(3-amino-3-oxopropyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-oxabicyclo[2.2.1]hept-2-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-methyl-1,3-thiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-1,3-thiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3R)-2-oxoazepanyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(cyclobutylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(butylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(5-hexynylamino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(2-furyl)-1-methylethyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-5-isoxazolyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isobutyl-1,3-thiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-(2-chlorophenyl)ethyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(2-oxo-1-pyrrolidinyl)propyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(cyclohexylmethyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(cyclopropylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(2-oxo-3-azepanyl)amino]propyl}-N³,N³-dipropylisophthalamide,N-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-3-(butylsulfonyl)benzamide,N¹-[(1S,2R)-1-benzyl-3-({2-[(2-ethylhexyl)oxy]ethyl}amino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[1-(4-hydroxyphenyl)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-(cycloheptylamino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[([1,1′-biphenyl]-2-ylmethyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(2-fluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(dimethylamino)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-1-naphthamide,N¹-[(1S,2R)-1-benzyl-3-({2-[({5-[(dimethylamino)methyl]-2-furyl}methyl)sulfanyl]ethyl}amino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-benzyl-3-({2-[(2-chloro-6-fluorobenzyl)sulfanyl]ethyl}amino)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[([1,1′-biphenyl]-4-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(1-naphthylamino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1H-imidazol-5-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-phenyl-1H-imidazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-imidazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(2-butyl-4-chloro-1H-imidazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-benzimidazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-hydroxy-1-naphthyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-oxo-4H-chromen-3-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-({[5-cyano-6-(methylsulfanyl)-2-pyridinyl]methyl}amino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N,N³-dipropylisophthalamide,[5-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)-2-furyl]methylacetate,N¹-[(1S,2R)-3-[(1-benzofuran-3-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({[1-(phenylsulfonyl)-1H-pyrrol-2-yl]methyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-pyrrol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(4-chloro-1-methyl-1H-pyrazol-3-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-phenyl-1H-pyrazol-4-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(5-chloro-2-thienyl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-phenoxy-2-thienyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-quinolinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-quinolinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-indol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1-benzyl-1H-indol-3-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-indol-3-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[({1-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl}methyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(2-butyl-1H-imidazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-amino)carbonyl]-5-[butyl(butyryl)amino]benzyldiethyl phosphate,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(cyanomethyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(hydroxymethyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³,N³-dipropyl-5-prop-1-ynylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-fluorobenzyl)amino]-2-hydroxypropyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(8-quinolinyl)isophthalamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4′-methoxy-N⁵,N⁵-dipropyl[1,1′-biphenyl]-3,5-dicarboxamide,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropyl[1,1′-biphenyl]-3,5-dicarboxamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropyl[1,1′-biphenyl]-3,5-dicarboxamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4′-[(dimethylamino)sulfonyl]-N⁵,N⁵-dipropyl-1,1′-biphenyl-3,5-dicarboxamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4′-[(dimethylamino)sulfonyl]-N⁵,N⁵-dipropyl-1,1′-biphenyl-3,5-dicarboxamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(3-thienyl)isophthalamide,N-{(1R,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-pentanoylbenzamide,N¹-(4-hydroxybutyl)-N³-{(1S)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N¹-propylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³-(3-hydroxypropyl)-5-methyl-N³-propylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3-(2,4-dimethylphenyl)propyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(4-methylphenyl)propyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N-{(1R,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-bromo-5-methylbenzamide,3-bromo-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methylbenzamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N¹,N¹-dipropylisophthalamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-(2-furyl)-5-methylbenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3′,5,5′-trimethyl-1,1′-biphenyl-3-carboxamide,3′-Acetyl-N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl[1,1′-biphenyl]-3-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3′-methoxy-5-methyl[1,1′-biphenyl]-3-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl[1,1′-biphenyl]-3-carboxamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(2-thienyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(3-thienyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3-methyl-5-(3-thienyl)benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-3-(3-thienyl)benzamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³,N⁵,N⁵-tetrapropylbenzene-1,3,5-tricarboxamide,N¹-{(1S,2R)-1-(3,5-Difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylbenzene-1,3,5-tricarboxamide,Ethyl3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-[(dipropylamino)carbonyl]benzoate,N¹-{(1S,2R)-2-Hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropylbenzene-1,3,5-tricarboxamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,5-Amino-N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(trifluoroacetyl)amino]isophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(thien-2-ylsulfonyl)amino]isophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(thien-2-ylcarbonyl)amino]isophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(methacryloylamino)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(2,2-dimethylpropanoyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(phenylsulfonyl)amino]-N³,N³-dipropylisophthalamide.N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-[propionyl(propyl)amino]benzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-bromo-5-methylbenzamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[butyl(propionyl)amino]-5-methylbenzamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-[(dipropylamino)carbonyl]benzoicacid,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-prop-1-ynylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-hydroxy-N3-methylisophthalamide,5-(aminosulfonyl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-2-methoxybenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-hydroxy-3-(pyrrolidin-1-ylcarbonyl)benzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(3,5-dimethylisoxazol-4-yl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1,3-thiazol-2-yl)isophthalamide,3-(cyclohexylcarbonyl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methylbenzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³-propylisophthalamide,3-[cyclohexyl(hydroxy)methyl]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methylbenzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(4-methyl-1,3-oxazol-2-yl)-N³,N³-dipropylisophthalamideN¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-1,2,4-oxadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(4-hydroxybut-1-ynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isopropyl-5-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-N³,5-dimethylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,5-dimethyl-N³-prop-2-ynylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isobutyl-5-methylisophthalamide,N¹-(sec-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-diethyl-5-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,5-dimethyl-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isopropyl-N³,5-dimethylisophthalamide,N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N¹,5-dimethylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isobutyl-N³,5-dimethylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-5-methyl-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-N³-isopropyl-5-methylisophthalamide,N¹,N¹-diallyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,3-(azepan-1-ylcarbonyl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylbenzamideN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(4-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(3-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-diisopropyl-5-methylisophthalamide,N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N¹-ethyl-5-methylisophthalamide,N¹-(cyclopropylmethyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N¹-propylisophthalamide,N¹-cyclohexyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N¹,5-dimethylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-methylphenyl)cyclopropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,andN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(trifluoromethyl)sulfonyl]amino}benzamide.60. A method of treatment according to claim 59 where the substitutedamine (X) is selected from the group consisting of:N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-furylmethyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(2-hydroxyethoxy)ethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-3-[(2-aminobenzyl)amino]-1-benzyl-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[2-(trifluoromethoxy)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,5-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethoxy)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[([1,1′-biphenyl]-3-ylmethyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,4-dichlorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-benzyl-2-hydroxy-3-[(3-methoxypropyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3,4-dimethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino)-1-methyl-2-oxoethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(isobutylamino)-1-methyl-2-oxoethyl]amino}propyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(isobutylamino)-1-methyl-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino)-1,1-dimethyl-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino)-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(isobutylamino)carbonyl]propyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1R)-1-[(isobutylamino)carbonyl]propyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(isobutylamino)-2-methyl-3-oxopropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1S)-1-benzyl-2-(isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(isobutylamino)carbonyl]-2-methylpropyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-pyridinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[(isobutylamino)carbonyl]butyl}amino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-1-(hydroxymethyl)-2-(isobutylamino)-2-oxoethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenylethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isopentylamino)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(cyclohexylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(butylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxypropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,(1R,3S)-5-{[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}-1,3-cyclohexanedicarboxylicacid,N¹-[(1S,2R)-3-[([1,1′-biphenyl]-3-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-⁵-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenylpropyl)amino]propyl}-⁵-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1,3-thiazol-5-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-thienylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-pyrazinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethoxy)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-fluorobenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-bromobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methoxy-N³,N³-dipropylisophthalamideN¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-chloro-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-fluoro-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}[1,1′-biphenyl]-3-carboxamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³-(2-methoxyethyl)-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1R)-1,2,3,4-tetrahydro-1-naphthalenylamino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1R)-3-{[3,5-bis(trifluoromethyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[2-fluoro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3-fluoro-5-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[4-fluoro-3-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[4-chloro-3-(trifluoromethyl)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N-{(1S)-1-benzyl-2-hydroxy-3-[(3-nitrobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-3-{[3-(difluoromethoxy)benzyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-ethoxybenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-bromo-4-fluorobenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,5-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethoxybenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-phenoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-methyl-1,3-thiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³-methyl-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,isomer B,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-furylmethyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(tetrahydro-3-furanylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-propoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-pyridinylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-hydroxy-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-methyl-1-(3-methylphenyl)ethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1S)-1,2,3,4-tetrahydro-1-naphthalenylamino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2,5-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[2-chloro-5-(trifluoromethyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-hydroxy-5-methylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,5-chloro-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1R)-1-(3-bromophenyl)ethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-hydroxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-cyano-N³,N³-dipropylisophthalamidehydrochloride,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,5-(aminosulfonyl)-N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1-pyrrolidinylsulfonyl)isophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylamino)sulfonyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(dimethylamino)sulfonyl]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-ethyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-tert-butyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-cyano-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3,4-dimethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-aminobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,5-chloro-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl-1-phenylethyl)amino]propyl}-N³,N³-bis(2-methoxyethyl)isophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(dimethylamino)benzyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4,5-dimethyl-2-furyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopentyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2S)-tetrahydro-2-furanylmethyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropenylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-propoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(hexylamino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzamide,methyl4-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)benzoate,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxyethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(5-isoxazolylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-oxabicyclo[2.2.1]hept-2-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-methyl-1,3-thiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-1,3-thiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(butylamino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(5-hexynylamino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(2-furyl)-1-methylethyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-5-isoxazolyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isobutyl-1,3-thiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[([1,1′-biphenyl]-4-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1H-imidazol-5-ylmethyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-phenyl-1H-imidazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(2-butyl-4-chloro-1H-imidazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-({[5-cyano-6-(methylsulfanyl)-2-pyridinyl]methyl}amino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,[5-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)-2-furyl]methylacetate,N¹-[(1S,2R)-3-[(1-benzofuran-3-ylmethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-indol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(5-chloro-2-thienyl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-indol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(1-benzyl-1H-indol-3-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1-methyl-1H-indol-3-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[(2-butyl-1H-imidazol-5-yl)methyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(cyanomethyl)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(hydroxymethyl)-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-ethynyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³,N³-dipropyl-5-prop-1-ynylisophthalamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4′-methoxy-N⁵,N⁵-dipropyl[1,1′-biphenyl]-3,5-dicarboxamidehydrochloride,N³-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropyl[1,1′-biphenyl]-3,5-dicarboxamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N⁵,N⁵-dipropyl[1,1′-biphenyl]-3,5-dicarboxamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4′-[(dimethylamino)sulfonyl]-N⁵,N⁵-dipropyl-1,1′-biphenyl-3,5-dicarboxamide,N³-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4′-[(dimethylamino)sulfonyl]-N⁵,N⁵-dipropyl-1,1′-biphenyl-3,5-dicarboxamide,N-{(1R,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-pentanoylbenzamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³-(3-hydroxypropyl)-5-methyl-N³-propylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³,N⁵,N⁵-tetrapropylbenzene-1,3,5-tricarboxamide,N¹-{(1S,2R)-1-(3,5-Difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylbenzene-1,3,5-tricarboxamide,ethyl3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-[(dipropylamino)carbonyl]benzoate,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,5-amino-N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(thien-2-ylsulfonyl)amino]isophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-[(thien-2-ylcarbonyl)amino]isophthalamide,N¹-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(methacryloylamino)-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-Benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(phenylsulfonyl)amino]-N³,N³-dipropylisophthalamide,5-bromo-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-phenylcyclopropyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-benzyl-2-hydroxy-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,3-[({(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}amino)carbonyl]-5-[(dipropylamino)carbonyl]benzoicacid,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-prop-1-ynylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-hydroxy-3-(pyrrolidin-1-ylcarbonyl)benzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1,3-thiazol-2-yl)isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³-propylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-1,2,4-oxadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(4-hydroxybut-1-ynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isopropyl-5-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-N³,5-dimethylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,5-dimethyl-N³-prop-2-ynylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isobutyl-5-methylisophthalamide,N¹-(sec-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-diethyl-5-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,5-dimethyl-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isopropyl-N³,5-dimethylisophthalamide,N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N¹,5-dimethylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-isobutyl-N³,5-dimethylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-5-methyl-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-N³-isopropyl-5-methylisophthalamide,N¹,N¹-diallyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,3-(azepan-1-ylcarbonyl)-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylbenzamideN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(4-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(3-hydroxypiperidin-1-yl)carbonyl]-5-methylbenzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-diisopropyl-5-methylisophthalamide,N¹-butyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N¹-ethyl-5-methylisophthalamide,N¹-(cyclopropylmethyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methyl-N¹-propylisophthalamide,N¹-cyclohexyl-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N¹,5-dimethylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-methylphenyl)cyclopropyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,andN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(trifluoromethyl)sulfonyl]amino}benzamide.61. A method of treatment according to claim 24 where the substitutedamine (X) is selected from the group consisting of:N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(2-propylpentanoyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(2-ethylpentanoyl)-5-methylbenzamide,N-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-methyl-5-(2-propylpentanoyl)benzamide,N-{(1S,2R)-1-benzyl-3-[(3-ethynylbenzyl)amino]-2-hydroxypropyl}-3-methyl-5-(2-propylpentanoyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(2-ethylbutanoyl)-5-methylbenzamide,N¹-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(2-propylpentanoyl)isophthalamide,N-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(2-ethylpentanoyl)-5-methylbenzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(2-propylpentanoyl)isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-(2-propylpentanoyl)isophthalamide,N-[(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propyl]-3-methyl-5-(2-propylpentanoyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-methyl-5-(2-propylpentanoyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-methyl-5-(2-propylpentanoyl)benzamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(3-pyridinyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(4-pyridinyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(1-propynyl)isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-(1-propynyl)isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-(2-propynyl)isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-(2-propynyl)isophthalamide,N¹-{(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(3-thienylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-[(1R)-2-(benzylamino)-1-hydroxyethyl]-3-butynyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(2-thienylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-3-(benzylamino)-1-[4-(benzyloxy)benzyl]-2-hydroxypropyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(cyclohexylmethyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(1-naphthylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,2,3,5-trideoxy-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-methoxybenzyl)amino]-1-S-phenyl-1-thio-D-erythro-pentitol,N¹-[(1S,2R)-3-(benzylamino)-1-(3-furylmethyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-methylbutyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(4-fluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(2-furylmethyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S)-1-[(1R)-2-(benzylamino)-1-hydroxyethyl]-3-methylbutyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(4-hydroxybenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-butynyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-butynyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,5-(benzylamino)-2,3,5-trideoxy-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-S-phenyl-1-thio-D-erythro-pentitol,N¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(4-hydroxybenzyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S)-1-[(1R)-2-(benzylamino)-1-hydroxyethyl]-3-methylbutyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-(benzylamino)-1-(3-furylmethyl)-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-methylbutyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-(benzylamino)-1-(4-fluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-(benzylamino)-1-(2-furylmethyl)-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(1-naphthylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(2-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-3-(benzylamino)-1-[4-(benzyloxy)benzyl]-2-hydroxypropyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-(benzylamino)-2-hydroxy-1-(3-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S)-1-[(1R)-2-(benzylamino)-1-hydroxyethyl]-3-butynyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-thienylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(2-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3-furylmethyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(4-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-((1S)-1-{(1R)-1-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-methylbutyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(4-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(1-naphthylmethyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-[3-(hydroxymethyl)benzyl]-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-[3-(hydroxymethyl)benzyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-[3-(hydroxymethyl)benzyl]-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-[4-(hydroxymethyl)benzyl]-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-[4-(hydroxymethyl)benzyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-[4-(hydroxymethyl)benzyl]-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-ethylbenzyl)amino]-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-fluoro-5-hydroxybenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-[3-(benzyloxy)-5-fluorobenzyl]-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-[3-(benzyloxy)-5-fluorobenzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-{[(2R)-1-ethylpyrrolidinyl]carbonyl}-5-methylbenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-{[(2S)-1-ethylpyrrolidinyl]carbonyl}-5-methylbenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(1-ethyl-1H-imidazol-2-yl)carbonyl]-5-methylbenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-[(1-ethyl-4-methyl-1H-imidazol-5-yl)carbonyl]-5-methylbenzamide,N¹-((1S,2S)-1-(3,5-difluorobenzyl)-2-hydroxy-2-{1-[(3-methoxybenzyl)amino]cyclopropyl}ethyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2S)-1-(3,5-difluorobenzyl)-2-{1-[(3-ethylbenzyl)amino]cyclopropyl}-2-hydroxyethyl)-5-methyl-N³,N³-dipropylisophthalamide,(1R,2R,3R)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N²,N²-dipropyl-1,2,3-cyclopropanetricarboxamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,N¹-{(1S,2R)-1-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-{methyl[(trifluoromethyl)sulfonyl]amino}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-{methyl[(trifluoromethyl)sulfonyl]amino}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-5-{propyl[(trifluoromethyl)sulfonyl]amino}isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[(phenylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-cyclopropylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1,3-thiazol-2-yl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1,3-oxazol-2-yl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,²R)-3-[(3-acetylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-acetylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-3-[(3-acetylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-(aminosulfonyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-acetylbenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-(methylsulfonyl)-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[3-(diethylamino)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(4-morpholinyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1-piperazinyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[3-(aminosulfonyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({3-[(dimethylamino)sulfonyl]benzyl}amino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1-piperidinylsulfonyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(methylsulfonyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(isopropylsulfonyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-{[3-(aminocarbonyl)benzyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({3-[(dimethylamino)carbonyl]benzyl}amino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-cyanobenzyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,3-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)phenylcarbamate,3-({[(2R,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-2-hydroxybutyl]amino}methyl)phenyldimethylcarbamate,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(1-propynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(3-methyl-1-butynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(2-propynyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(5-isobutyl-1,3,4-oxadiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(5-ethyl-1,3,4-oxadiazol-2-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(5-ethyl-1,3,4-thiadiazol-2-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(5-isobutyl-1,3,4-thiadiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(3-ethyl-1,2,4-thiadiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(3-isobutyl-1,2,4-thiadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(3-isobutyl-1,2,4-oxadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[3-(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-1,3-oxazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isobutyl-1,3-oxazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-isobutyl-1,3,4-oxadiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-isobutyl-1,3,4-thiadiazol-2-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(5-ethyl-1,3,4-thiadiazol-2-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(5-ethyl-1,3,4-oxadiazol-2-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(3-ethyl-1,2,4-thiadiazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-1,2,4-thiadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(3-isobutyl-1,2,4-oxadiazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-2H-tetraazol-5-yl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isobutyl-2H-tetraazol-5-yl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethyl-4-pyrimidinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(2-isopropyl-4-pyrimidinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(2-ethynyl-4-pyrimidinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(6-isopropyl-4-pyrimidinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({[6-(dimethylamino)-4-pyrimidinyl]methyl}amino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({[2-(dimethylamino)-4-pyrimidinyl]methyl}amino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({[4-(dimethylamino)-2-pyrimidinyl]methyl}amino)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-isopropyl-2-pyrimidinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4-ethyl-2-pyrimidinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(5-ethyl-3-pyridazinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(5-isopropyl-3-pyridazinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(6-isopropyl-4-pyridazinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(6-ethyl-4-pyridazinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(6-ethyl-2-pyrazinyl)methyl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(6-isopropyl-2-pyrazinyl)methyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3,4,5-trifluorobenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-2-hydroxy-1-(3,4,5-trifluorobenzyl)-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-2-hydroxy-1-(2,3,5,6-tetrafluorobenzyl)-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2,3,5,6-tetrafluorobenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1R,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl]amino}propyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1R,2S)-6-ethyl-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-2-hydroxypropyl)-5-methyl-N³,N³-dipropylisophthalamide,N¹-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1R,2S)-6-ethyl-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-2-hydroxypropyl)-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(1H-indol-5-ylmethyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-3-[(3-ethylbenzyl)amino]-2-hydroxy-1-(1H-indol-5-ylmethyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-methylbenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(3-methylbenzyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[3-(trifluoromethyl)benzyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[3-(trifluoromethyl)benzyl]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-[3-fluoro-5-(trifluoromethyl)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-[3-fluoro-5-(trifluoromethyl)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[3-(trifluoromethoxy)benzyl]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-[3-(trifluoromethoxy)benzyl]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(3-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(3-hydroxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(4-methylbenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(4-methylbenzyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(4-fluoro-3-methylbenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(4-fluoro-3-methylbenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(4-chlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(4-chlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(3-methoxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{((1S,2R)-2-hydroxy-1-(3-methoxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(4-methoxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(4-methoxybenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3-chloro-5-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-chloro-5-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(4-chloro-3-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(4-chloro-3-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3,5-dichlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-dichlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-[4-(dimethylamino)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-[4-(dimethylamino)benzyl]-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3-chlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-chlorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-fluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-2-hydroxy-1-(4-isopropylbenzyl)-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-2-hydroxy-1-(4-isopropylbenzyl)-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3-fluoro-4-methylbenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-fluoro-4-methylbenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-{(1S,2R)-1-(3-fluoro-4-methoxybenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3-fluoro-4-methoxybenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-methoxy-5-methylbenzyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-2-hydroxy-3-[(3-methoxybenzyl)amino]-1-(2-methoxy-5-methylbenzyl)propyl]-N³,N³-dipropyl-1,3,5-benzenetricarboxamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(1-pyrrolidinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl})-4-hydroxy-3-(1-pyrrolidinylcarbonyl)benzamide,N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-1-methylethyl]amino}-2-hydroxypropyl)-4-hydroxy-3-(1-pyrrolidinylcarbonyl)benzamide,N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-4-hydroxy-3-(1-pyrrolidinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-3-(1-piperidinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(1-piperidinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(4-morpholinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(4-morpholinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-3-(1-piperazinylcarbonyl)benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-3-(1-piperazinylcarbonyl)benzamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-N³-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³-ethyl-4-hydroxyisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-4-hydroxyisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-N³-ethyl-4-hydroxyisophthalamide,N³-(cyclopropylmethyl)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-hydroxyisophthalamide,N³-(cyclopropylmethyl)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxyisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-isobutylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-isobutyl-N³-methylisophthalamide,N³-(cyclopropylmethyl)-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-methylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³-methyl-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-N³-methyl-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N³-ethyl-4-hydroxy-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³-ethyl-4-hydroxy-N³-propylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-4-hydroxy-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-4-hydroxy-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-4-hydroxy-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(ethylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-[(propylsulfonyl)amino]isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(isopropylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(isobutylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-[(thien-2-ylsulfonyl)amino]isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(2-furylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-[(1,3-thiazol-5-ylsulfonyl)amino]isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(1,3-oxazol-5-ylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(1,3-oxazol-4-ylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-[(1,3-thiazol-4-ylsulfonyl)amino]isophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-[(phenylsulfonyl)amino]-N³,N³-dipropylisophthalamide,5-{[(5-cyanopyridin-2-yl)sulfonyl]amino}-N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide,N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-N³,N³-dipropyl-5-({[5-(trifluoromethyl)pyridin-2-yl]sulfonyl}amino)isophthalamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-({[5-(trifluoromethyl)pyridin-2-yl]sulfonyl}amino)benzamide,3-{[(5-cyanopyridin-2-yl)sulfonyl]amino}-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(phenylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(methylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(ethylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(propylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(isobutylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(isopropylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(1-ethylpropyl)sulfonyl]amino}benzamide,3-[(cyclohexylsulfonyl)amino]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(1-propylbutyl)sulfonyl]amino}benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(thien-2-ylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(2-furylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(isoxazol-5-ylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(isoxazol-3-ylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(3-furylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(thien-3-ylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1,3-thiazol-4-ylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1,3-thiazol-5-ylsulfonyl)amino]benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-[(1,3-thiazol-2-ylsulfonyl)amino]benzamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isopentylamino)propyl]-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,N¹-[(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-N³,N³-dipropyl-5-{[(trifluoromethyl)sulfonyl]amino}isophthalamide,N¹-[(1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(isopentylamino)propyl]-5-[(methylsulfonyl)amino]-N³,N³-dipropylisophthalamide,N¹-(tert-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isophthalamide,N¹-(tert-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylisophthalamide,5-bromo-N¹-(tert-butyl)-N³-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isophthalamide,3-tert-butoxy-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}benzamide,3-tert-butoxy-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-methylbenzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-{[(trifluoromethyl)sulfonyl]amino}benzamide,N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(trifluoromethoxy)benzamide,andN-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-methyl-5-(trifluoromethoxy)benzamide.62. A pharmaceutical composition which comprises a substituted amine offormula (X)

where R₁ is: —(CH₂)_(n1)—(R_(1-aryl)) where n₁ is zero or one and whereR_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl and indenyl, indenyl,dihydronaphthalyl, or tetralinyl optionally substituted with one, two,three, or four of the following substituents on the aryl ring: (A) C₁–C₆alkyl optionally substituted with one, two or three substituentsselected from the group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I,—OH, —SH, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, —C≡N, —CF₃, C₁–C₃ alkoxy, (B) C₁–C₆ alkenyl with one or twodouble bonds, optionally substituted with one, two or three substituentsselected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃,C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H orC₁–C₆ alkyl, (C) C₂–C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, (D)—F, Cl, —Br or —I, (F) —C₁–C₆ alkoxy optionally substituted with one,two, or three of: —F, (G) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) areas defined below, (H) —OH, (I) —C≡N, (J) C₃C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, (K)—CO—(C₁–C₄ alkyl), (L) —SO₂—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are as defined above, (M) —CO—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are as defined above, or (N) —SO₂—(C₁–C₄ alkyl), where R₂ is: (I)—H,(II) C₁–C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁–C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above, (III) —(CH₂)₀₋₄R₂₋₁ where R₂₋₁is R_(1-aryl) or R_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl)are as defined above; (IV) C₂–C₆ alkenyl with one or two double bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl, (V) C₁–C₆ alkynyl with one ortwo triple bonds, optionally substituted with one, two or threesubstituents selected from the group consisting of —F, —Cl, —OH, —SH,—C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b)are —H or C₁–C₆ alkyl, or (VI) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of —F, —Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl; whereR₃ is: (I)—H, (II) C₁–C₆ alkyl, optionally substituted with one, two orthree substituents selected from the group consisting of C₁–C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (III)—(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl) or R_(1-heteroaryl) whereR_(1-aryl) and R_(1-heteroaryl) are as defined above; (IV) C₂–C₆ alkenylwith one or two double bonds, (V) C₂–C₆ alkynyl with one or two triplebonds, or (VI) —(CH₂)₀₋₄—C₃C₇ cycloalkyl, optionally substituted withone, two or three substituents selected from the group consisting of —F,—Cl, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are —H or C₁–C₆ alkyl,  and where R₂ and R₃ aretaken together with the carbon to which they are attached to form acarbocycle of three, four, five, six or seven carbon atoms, optionallywhere one carbon atom is replaced by a heteroatom selected from thegroup consisting of —O—, —S—, —SO₂—, and —NR_(N-2)—, where R_(N-2) is asdefined below; where R_(N) is: (I) R_(N-1)—X_(N)— where X_(N) is —CO—;where R_(N-1) is selected from the group consisting of: (A) R_(N-aryl)where R_(N-aryl) is phenyl optionally substituted with one, two or threeof the following substituents which can be the same or different andare: (1) C₁–C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁–C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, and —NR_(1-a)R_(1-b) whereR_(1-a) and R_(1-b) are as defined above, (2) —OH, (3) —NO₂, (4) —F,—Cl, —Br, or —I, (5) —CO—OH, (6) —C≡N, (7) —(CH₂)₀₋₄—CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same or different and are selectedfrom the group consisting of: (a) —H, (b) —C₁–C₆ alkyl optionallysubstituted with one substitutent selected from the group consisting of:(i) —OH, and (ii) —NH₂, (c) —C₁–C₆ alkyl optionally substituted with oneto three —F, —Cl, —Br, or —I, (d) —C₃–C₇ cycloalkyl, (e) —(C₁–C₂alkyl)—(C₃–C₇ cycloalkyl), (f) —(C₁–C₆ alkyl)—O—(C₁–C₃ alkyl), (g)—C₂–C₆ alkenyl with one or two double bonds, (h) —C₂–C₆ alkynyl with oneor two triple bonds, (i) —C₁–C₆ alkyl chain with one double bond and onetriple bond, (j) —R_(1-aryl) where R_(1-aryl) is as defined above, and(k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above, (8)—(CH₂)₀₋₄—CO—(C₁–C₁₂ alkyl), (9) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkenyl with one,two or three double bonds), (10) —(CH₂)₀₋₄—CO—(C₂–C₁₂ alkynyl with one,two or three triple bonds), (11) —(CH₂)₀₋₄—CO—(C₃–C₇ cycloalkyl), (12)—(CH₂)₀₋₄—CO—R_(1-aryl) where R_(1-aryl) is as defined above, (13)—(CH₂)₀₋₄—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as definedabove, (14) —(CH₂)₀₋₄—CO—R_(1-heterocycle) where R_(1-heterocycle) is asdefined above, (15) —(CH₂)₀₋₄—CO—R_(N-4) where R_(N-4) is selected fromthe group consisting of morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinylS-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinylwhere each group is optionally substituted with one, two, three, or fourof: C₁–C₆ alkyl, (16) —(CH₂)₀₋₄—CO—O—R_(N-5) where R_(N-5) is selectedfrom the group consisting of: (a) C₁–C₆ alkyl, (b)—(CH₂)₀₋₂—(R_(1-aryl)) where R_(1-aryl) is as defined above, (c) C₂–C₆alkenyl containing one or two double bonds, (d) C₂–C₆ alkynyl containingone or two triple bonds, (e) C₃–C₇ cycloalkyl, and (f)—(CH₂)₀₋₂—(R_(1-heteroaryl)) where R_(1-heteroaryl) is as defined above,(17) —(CH₂)₀₋₄—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are asdefined above, (18) —(CH₂)₀₋₄—SO—(C₁–C₈ alkyl), (19)—(CH₂)₀₋₄—SO₂—(C₁–C₁₂ alkyl), (20) —(CH₂)₀₋₄—SO₂—(C₃–C₇ cycloalkyl),(21) —(CH₂)₀₋₄—N(H or R_(N-5))—CO—O—R_(N-5) where R_(N-5) can be thesame or different and is as defined above, (22) —(CH₂)₀₋₄—N(H orR_(N-5)) —CO—N(R_(N-5))₂, where R_(N-5) can be the same or different andis as defined above, (23) —(CH₂)₀₋₄—N—CS—N(R_(N-5))₂, where R_(N-5) canbe the same or different and is as defined above, (24) —(CH₂)₀₋₄—N(—H orR_(N-5))—CO—R_(N-2) where R_(N-5) and R_(N-2) can be the same ordifferent and are as defined above, (25) —(CH₂)₀₋₄—NR_(N-2)R_(N-3) whereR_(N-2) and R_(N-3) can be the same or different and are as definedabove, (26) —(CH₂)₀₋₄—R_(N-4) where R_(N-4) is as defined above, (27)—(CH₂)₀₋₄—O—CO—(C₁–C₆ alkyl), (28) —(CH₂)₀₋₄—O—P(O)—(OR_(N-aryl-1))₂where R_(N-aryl-1) is —H or C₁–C₄ alkyl, (29) —(CH₂)₀₋₄—O—CO—N(R_(N-5))₂where R_(N-5) is as defined above, (30) —(CH₂)₀₋₄—O—CS—N(R_(N-5))₂ whereR_(N-5) is as defined above, (31) —(CH₂)₀₋₄—O—(R_(N-5))₂ where R_(N-5)is as defined above, (32) —(CH₂)₀₋₄—O—(R_(N-5))₂—COOH where R_(N-5) isas defined above, (33) —(CH₂)₀₋₄—S—(R_(N-5))₂ where R_(N-5) is asdefined above, (34) —(CH₂)₀₋₄—O—(C₁–C₆ alkyl optionally substituted withone, two, three, four, or five —F), (35) C₃–C₇ cycloalkyl, (36) C₂–C₆alkenyl with one or two double bonds optionally substituted with C₁–C₃alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (37)C₂–C₆ alkynyl with one or two triple bonds optionally substituted withC₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₃ alkoxy, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (38)—(CH₂)₀₋₄—N(—H or R_(N-5))—SO₂—R_(N-2) where R_(N-5) and R_(N-2) can bethe same or different and are as described above, or (39)—(CH₂)₀₋₄—C₃–C₇ cycloalkyl, where R_(C) is: (I) —C₁–C₁₀ alkyl optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃,C₁–Calkoxy, —O-phenyl, —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, —OC═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, —S(═O)₀₋₂ R_(1-a) where R_(1-a) is as defined above,—NR_(1-a)C═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, —C═ONR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, and —S(═O)₂NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (II) —(CH₂)₀₋₃—(C₃–C₈) cycloalkyl where cycloalkyl can beoptionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁–C₆ alkoxy, —O-phenyl, —CO—OH, —CO—O—(C₁–C₄ alkyl), and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (III)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl) where R_(C-x) and R_(C-y) are —H, C₁–C₄alkyl optionally substituted with one or two —OH, C₁–C₄ alkoxyoptionally substituted with one, two, or three of: —F, —(CH₂)₀₋₄—C₃–C₇cycloalkyl, C₂–C₆ alkenyl containing one or two double bonds, C₂–C₆alkynyl containing one or two triple bonds, phenyl-, and where R_(C-x)and R_(C-y) are taken together with the carbon to which they areattached to form a carbocycle of three, four, five, six, or seven carbonatoms, optionally where one carbon atom is replaced by a heteroatomselected from the group consisting of —O—, —S—, —SO₂—, and —NR_(N-2)—and R_(C-aryl) is the same as R_(N-aryl); (IV)—(CR_(C-x)R_(C-y))₀₋₄R_(C-heteroaryl) where R_(C-heteroaryl) is the sameas R_(N-heteroaryl) and R_(C-x) and R_(C-y) are as defined above, (V)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-aryl) where R_(C-aryl), R_(C-x)and R_(C-y) are as defined above, (VI)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-heteroaryl) where R_(C-aryl),R_(C-heteroaryl), R_(C-x) and R_(C-y) are as defined above, (VII)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-aryl) whereR_(C-heteroaryl), R_(C-aryl), R_(C-x) and R_(C-y) are as defined above,(VIII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-heteroaryl) whereR_(C-heteroaryl), R_(C-x) and R_(C-y) are as defined above, (IX)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-aryl)—R_(C-heterocycle) where R_(C-aryl),R_(C-x) and R_(C-y) are as defined above, and R_(C-heterocycle) is thesame as R_(N-heterocycle), (X)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heteroaryl)—R_(C-heterocycle) whereR_(C-heteroaryl), R_(C-heterocycle), R_(C-x) and R_(C-y) are as definedabove, (XI) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-aryl) whereR_(C-heterocycle), R_(C-aryl), R_(C-x) and R_(C-y) are as defined above,(XII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-heteroaryl) whereR_(C-heterocycle), R_(C-heteroaryl), R_(C-x) and R_(C-y) are as definedabove, (XIII) —(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle)—R_(C-heterocycle)where R_(C-heterocycle), R_(C-x) and R_(C-y) are as defined above, (XIV)—(CR_(C-x)R_(C-y))₀₋₄—R_(C-heterocycle) where R_(C-heterocycle), R_(C-x)and R_(C-y) are as defined above, (XV)—[C(R_(C-1))(R_(C-2))]₁₋₃—CO—N—(R_(C-3))₂ where R_(C-1) and R_(C-2) arethe same or different and are selected from the group consisting of: (A)—H, (B) —C₁–C₆ alkyl, optionally substituted with one, two or threesubstituents selected from the group consisting of C₁–C₃ alkyl, —F, —Cl,—Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O— phenyl, and—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (C)C₂–C₆ alkenyl with one or two double bonds, optionally substituted withone, two or three substituents selected from the group consisting ofC₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O—phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (D) C₂–C₆ alkynyl with one or two triple bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areas defined above, (E) —(CH₂)₁₋₂—S(O)₀₋₂—(C₁–C₆ alkyl), (F)—(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionally substituted with one, two orthree substituents selected from the group consisting of C₁–C₃ alkyl,—F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O— phenyl,—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (G)—(C₁–C₄ alkyl)—R_(C′-aryl) where R_(C′-aryl) is as defined forR_(1-aryl), (H) —(C₁–C₄ alkyl)—R_(C-heteroaryl) where R_(C-heteroaryl)is as defined above, (I) —(C₁–C₄ alkyl)—R_(C-heterocycle) whereR_(C-heterocycle) is as defined above, (J) —R_(C-heteroaryl) whereR_(C-heteroaryl) is as defined above, (K) R_(C-heterocycle) whereR_(C-heterocycle) is as defined above, (M)—(CH₂)₁₋₄—R_(C-4)—(CH₂)₀₋₄—R_(C′-aryl) where R_(C-4) is —O—, —S— or—NR_(C-5)— where R_(C-5) is C₁–C₆ alkyl, and where R_(C′-aryl) is asdefined above, (N) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₀₋₄—R_(C-heteroaryl) whereR_(C-4) and R_(C-heteroaryl) are as defined above, and (O) —R_(C′-aryl)where R_(C′-aryl) is as defined above, and where R_(C-3) is the same ordifferent and is: (A) —H, (B) —C₁–C₆ alkyl optionally substituted withone, two or three substituents selected from the group consisting ofC₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, —O—phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as definedabove, (C) C₂–C₆ alkenyl with one or two double bonds, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, CF₃, C₁–C₆alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areas defined above, (D) C₂–C₆ alkynyl with one or two triple bonds,optionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁–C₆ alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, (E) —(CH₂)₀₋₄—C₃–C₇ cycloalkyl, optionallysubstituted with one, two or three substituents selected from the groupconsisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) areas defined above, (F) —R_(C′-aryl) where R_(C′-aryl) is as definedabove, (G) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above,(H) —R_(C-heterocycle) where R_(C-heterocycle) is as defined above, (I)—(C₁–C₄ alkyl)—R_(C′-aryl) where R_(C′-aryl) is as defined above, (J)—(C₁–C₄ alkyl)—R_(C-heteroaryl) where R_(C-heteroaryl) is as definedabove, or (K) —(C₁–C₄ alkyl)—R_(C-heterocycle) where R_(C-heterocycle)is as defined above, (XVI) —CH(R_(C-aryl))₂ where R_(C-aryl) are thesame or different and are as defined above, (XVII)—CH(R_(C-heteroaryl))₂ where R_(C-heteroaryl) are the same or differentand are as defined above, (XVIII) —CH(R_(C-aryl))(R_(C-heteroaryl))where R_(C-aryl) and R_(C-heteroaryl) are as defined above, (XIX)-cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused to R_(C-aryl) orR_(C-heteroaryl or R) _(C-heterocycle) where R_(C-aryl) orR_(C-heteroaryl) or R_(C-heterocycle) are as defined above where onecarbon of cyclopentyl, cyclohexyl, or -cycloheptyl is optionallyreplaced with NH, NR_(N-5), O, or S(═O₀₋₂, and where cyclopentyl,cyclohexyl, or -cycloheptyl can be optionally substituted with one ortwo —C₁–C₃ alkyl, —F, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy, ═O, or—NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are as defined above, (XX)C₂–C₁₀ alkenyl containing one or two double bonds optionally substitutedwith one, two or three substituents selected from the group consistingof C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF₃, C₁–C₆ alkoxy,—O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) and R_(1-b) are asdefined above, (XXI) C₂–C₁₀ alkynyl containing one or two triple bondsoptionally substituted with one, two or three substituents selected fromthe group consisting of C₁–C₃ alkyl, —F, —Cl, —Br, —I, —OH, —SH, —C≡N,—CF₃, C₁–C₆ alkoxy, —O— phenyl, and —NR_(1-a)R_(1-b) where R_(1-a) andR_(1-b) are as defined above, (XXI)—(CH₂)₀₋₂—CHR_(C-6)—(CH₂)₀₋₁—R_(C-aryl) where R_(C-aryl) is as definedabove and R_(C-6) is —(CH₂)₀₋₆—OH, (XXII)—(CH₂)₀₋₁—CHR_(C-6)—(CH₂)₀₋₁—R_(C-heteroaryl) where R_(C-heteroaryl) andR_(C-6) is as defined above, (XXIII) —CH(—R_(C-aryl) orR_(C-heteroaryl))—CO—O(C₁–C₄ alkyl) where R_(C-aryl) andR_(C-heteroaryl) are as defined above, (XXIV)—CH(—CH₂—OH)—CH(—OH)-phenyl-NO₂, (XXV) (C₁–C₆ alkyl)—O—(C₁–C₆ alkyl)—OH,(XXVII) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂, (XXVIII) —H, or (XXIX)—(CH₂)₀₋₆—C(═NR_(1-a))(NR_(1-a)R_(1-b)) where R_(1-a) and R_(1-b) are asdefined above; or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable inert carriers.
 63. A method forinhibiting beta-secretase activity, comprising exposing saidbeta-secretase to an effective inhibitory amount of a compound offormula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 64. The method of claim 63,wherein said beta-secretase is exposed to said compound in vitro. 65.The method of claim 63, wherein said beta-secretase is exposed to saidcompound in a cell.
 66. The method of claim 65, wherein said cell is inan animal.
 67. The method of claim 66, wherein said animal is a human.68. A method for inhibiting cleavage of amyloid precursor protein (APP),in a reaction mixture, at a site between Met596 and Asp597, numbered forthe APP-695 amino acid isotype; or at a corresponding site of an isotypeor mutant thereof, comprising exposing said reaction mixture to aneffective inhibitory amount of a compound of formula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 69. The method of claim 68,wherein said cleavage site is between Met652 and Asp653, numbered forthe APP-751 isotype; between Met 671 and Asp 672, numbered for theAPP-770 isotype; between Leu596 and Asp597 of the APP-695 SwedishMutation; between Leu652 and Asp653 of the APP-751 Swedish Mutation; orbetween Leu671 and Asp672 of the APP-770 Swedish Mutation.
 70. Themethod of claim 68, wherein said reaction mixture is exposed in vitro.71. The method of claim 68, wherein said reaction mixture is exposed ina cell.
 72. The method of claim 71, wherein said cell is an animal cell.73. The method of claim 72, wherein said cell is a human cell.
 74. Amethod for inhibiting production of amyloid beta peptide (A beta) in acell, comprising administering to said cell an effective inhibitoryamount of a compound of formula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 75. The method of claim 74,wherein said administering is to an animal.
 76. The method of claim 75,wherein said administering is to a human.
 77. A method for inhibitingthe production of beta-amyloid plaque in an animal, comprisingadministering to said animal an effective inhibitory amount of acompound of formula

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 78. The method of claim 77,wherein said animal is a human.
 79. A method for treating or preventinga disease characterized by beta-amyloid deposits in the brain comprisingadministering to a patient an effective therapeutic amount of a compoundof formula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 80. The method of claim 79,wherein said therapeutic amount is in the range of from about 0.1 toabout 1000 mg/day.
 81. The method of claim 79, wherein said thereapeuticamount is in the range of from about 15 to about 1500 mg/day.
 82. Themethod of claim 81, wherein said thereapeutic amount is in the range offrom about 1 to about 100 mg/day.
 83. The method of claim 82, whereinsaid thereapeutic amount is in the range of from about 5 to about 50mg/day.
 84. The method of claim 79, wherein said disease is Alzheimer'sdisease.
 85. The method of claim 79, wherein said disease is MildCognitive Impairment, Down's Syndrome, or Hereditary CerebralHemmorrhage with Amyloidosis of the Dutch Type.
 86. A compositioncomprising beta-secretase complexed with a compound of formula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 87. A method for producing abeta-secretase complex comprising: exposing beta-secretase, in areaction mixture under conditions suitable for the production of saidcomplex, to a compound of formula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 88. The method of claim 87,where said exposing is in vitro.
 89. The method of claim 87, whereinsaid reaction mixture is a cell.
 90. A kit comprising component partscapable of being assembled, wherein at least one component partcomprises, enclosed in a container, a compound of formula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 91. The kit of claim 90,wherein said compound is lyophilized and at least one further componentpart comprises a diluent.
 92. A kit comprising a plurality ofcontainers, each container comprising one or more unit dose of acompound of formula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 93. The kit of claim 92,wherein each container is adapted for oral delivery and comprises atablet, gel, or capsule.
 94. The kit of claim 93, wherein each containeris adapted for parenteral delivery and comprises a depot product,syringe, ampoule, or vial.
 95. The kit of claim 93, wherein eachcontainer is adapted for topical delivery and comprises a patch,medipad, ointment, or cream.
 96. A kit comprising one or moretherapeutic agent selected from the group consisting of an antioxidant,an anti-inflammatory, a gamma secretase inhibitor, a neurotrophic agent,an acetylcholinesterase inhibitor, a statin, an A beta peptide, and ananti-A beta antibody; and a compound of formula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 97. A composition comprisingan inert diluent or edible carrier; and a compound of formula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 98. The composition of claim97, wherein said carrier is an oil.
 99. A composition comprising abinder, excipient, disintegrating agent, lubricant, or gildant; and acompound of formula (X)

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 100. A composition comprisinga compound of formula

where R₁, R₂, R₃, R_(N) and R_(C) are as defined in claim 1, or apharmaceutically acceptable salt thereof, and where the compound isdisposed in a cream, ointment, or patch.